THE  SPIEIT  OF  ORGANIC  CHEMISTRY 


THE  SPIRIT 


OF 


ORGANIC   CHEMISTRY 


AN  INTRODUCTION  TO   THE  CURRENT 
LITERATURE  OF  THE  SUBJECT 


BY 

ARTHUR   LACHMAN 

V* 

(B.8.,  CALIF.  ;  PH.D.,  MUNICH) 
PROFESSOR  OF  CHEMISTRY  IN  THE  UNIVERSITY  OF  OREGON 


WITH  AN  INTRODUCTION  BY 
PAUL  C.  FREER,  M.D.,  PH.D. 

PROFESSOR  OF  GENERAL  CHEMISTJRY  IN   THE 
UNIVERSITY  OF  MICHIGAN 


Nefo  gorft 
THE  MACMILLAN  COMPANY 

LONDON;  M^MlLi:  AN  &  CCh,"  LTD. 


All  rights  reserved 


V 


COPTBIGHT,   1899, 

BY  THE  MACMILLAN  COMPANY. 


Norfoootr 

Bpfjvick&'Smith 


ERRATA 

Page  50,  line  4,  read  "  of  distance  "  in  place  of  "  on 
distance." 

Page  129,  line  4  below  Chart  I.,  read  "formula"  in 
place  of  "  formulae." 

Page  131,  corrected  cut :  — 


Page  146,  footnote  2,  omit  c  in  Monatsh. 
Page  162,  corrected  cut :  — 


«-4-   C    -4-c  c-4-    G    4-fc  c-4-    C    4-a 

Y     X      T 


Page  173,  line  12,  2d  formula,  read  «C6H5-C  =  NOH  " 
instead  of  «  C6H5  =  C  =  NOH." 

Page  182,  line  10  from  bottom,  read  "NX  "  instead  of 
"NX2." 

Page  202,  line  2  from  bottom,  2d  part  of  formula,  read 
«(CH3)3N-0"  instead  of  "  (CH3)3-N 0." 

Page  209,  line  13,  read  "KHS04"  instead  of  «  K2HS04." 


PREFACE 

THIS  book  is  intended  primarily  as  a  supplement 
to  text-books  of  organic  chemistry.  Text-books  tell 
us  the  important  facts  of  a  science  and  the  conclu- 
sions to  which  these  have  led  ;  their  aim  is  to  present 
the  subject  and  its  principles, as  a  complete  whole  — 
their^mphasis  is  laid  upon  unity  and  coordination. 
But  .£|  science  is  a  living,  growing  thing,  which  at 
any  given  moment  is  far  from  being  unified  and 
coordinated.  The  beginner,  coming  upon  the  ten 
thousand  pages  which  mark  the  annual  growth  of  or- 
ganic chemistry,  cannot  but  be  bewildered.  Theories 
stated  conclusively  by  his  text-book  he  finds  assailed 
and  refuted ;  facts  unmask  themselves  which  he  is 
tempted  to  regard  as  impossible.  Why  this  cease- 
less activity  ?  Are  the  text-books  wrong  ?  Are  these 
ten  thousand  pages  of  vital  importance,  and  must 
one  read  them  all  if  he  hopes  to  keep  up  with  the 
march  of  science?  Why  is  there  so  much  "re- 
search"? To  all  of  these  questions  the  student 
finds  no  answer  ready  to  hand ;  this  little  compila- 
tion aims  to  satisfy  his  curiosity. 

The  scientific  investigator  must  test  his  theories 
by  the  light  of  special  facts.  His  general  ideas 
resolve  themselves  into  a  number  of  component 
ideas ;  research,  in  the  last  analysis,  consists  of  a 
series  of  detailed  problems,  more  or  less  extended. 

v 


VI  PREFACE 

• 

A  general  principle  of  organic  chemistry,  therefore, 
must  be  examined  by  the  side  of  definite  experiments 
—  an  experiment  is  the  very  essence  of  definiteness. 
The  present  state  of  its  development  is  best  dis- 
cerned by  following  its  historic  evolution,  by  a  study 
of  its  origin  and  of  its  career.  j~~X  number  of  the 
chief  problems  of  the  science  have  been  taken  up 
in  this  manner,  and  will  be  found  to  answer  many 
of  the  questions  that  perplex  the  rising  chemist: 
problems  which  have  had  no  history,  which  h£ve" 
been  established  in  a  single  masterly  research,  mani- 
festly do  not  fall  within  the  scope  of  this  collection ; 
they  are  sufficiently  treated  in  the  text-books.  No 
great  dema»d  has  been  made  upon  previous  famil- 
iarity with  the  subject.  A  certain  danger  lies  in  the 
attempt  to  bring  the  topics  up  to  date  ;  but  wherever 
possible  this  risk  has  been  incurred.  To  avoid  con- 
fusion, formulae  antedating  present  structure-theories 
have  been  transposed  into  their  modern  equivalents. 
A  word  of  apology  may  be  necessary  for  the  au- 
thorship of  this  somewhat  critical  volume.  There 
can  be  no  doubt  that  it  would  grace  the  pen  of  a 
master  better  than  that  of  a  tyro.  But  the  leaders 
in  the  van  of  progress  do  not  heed  the  wants  of  the 
struggling  columns  in  their  rear  —  and  so  we  must 
needs  help  ourselves.  The  habit  of  browsing  among 
the  earlier  numbers  of  our  chemical  journals,  origi- 
nally formed  for  self-improvement,  has  been  the 
immediate  suggestion  for  the  present  work.  The 
detailed  study  of  treatises  of  bygone  periods  has 
been  its  own  reward ;  and  this  little  volume  will  fail 
of  its  purpose  if  its  readers  are  not  induced  to  seek 
out  the  sources  of  our  present  knowledge. 


PREFACE  Vll 

The  materials  employed  during  the  preparation  of 
the  various  chapters  are  sufficiently  indicated  in  the 
body  of  the  work.  Wherever  use  has  been  made  of 
existing  summaries  the  fact  has  been  mentioned ; 
but  the  total  treatment  of  each  subject  has  always 
been  evolved  independently.  The  attempt  has  been 
made  to  quote  the  original  authorities  for  all  impor- 
tant statements ;  and  unsupported  comments  and 
criticisms  must  be  credited,  or,  it  may  be,  blamed, 
to  the  author.  The  author  must  also  bear  the 
responsibility  for  his  choice  of  material ;  the  main 
object  of  the  book  being  didactic,  the  individual  chap- 
ters are  by  no  means  to  be  Regarded  as  bibliographies. 

Aside  from  the  main  object  just  stated,  the  method 
of  treatment  here  adopted  may  serve  other  desirable 
ends.  In  the  first  place,  the  personal  element  in 
science  would  appear  to  be  far  too  much  neglected. 
Nothing  brings  home  to  the  student  the  living,  grow- 
ing nature  of  his  subject  more  than  to  be  familiar 
with  the  names  of  those  who  have  brought  it  to  its 
present  stage,  or  perchance  to  hear  his  instructors 
tell  of  their  ways  in  the  laboratory -and  the  lecture- 
room.  The  share  of  credit  due  to  each  investigator 
in  the  various  topics  under  consideration  has  been 
strongly  emphasized. 

Secondly,  students  are  not  sufficiently  encouraged 
to  read  the  current  literature ;  and  its  vastness 
proves  an  effective  damper  if  no  guide  to  its  mazes 
be  at  hand.  As  most  of  the  subjects  selected  here 
are  still  open  questions,  as  the  names  of  the  investi- 
gators engaged  upon  them  are  prominently  put  for- 
ward, and  as  the  journals  in  which  these  chemists 
are  accustomed  to  publish  their  results  are  invariably 


viii  PEEFACE 

quoted,  no  difficulty  should  be  experienced  in  fol- 
lowing up  these  topics,  at  any  rate.  Once  the  habit 
of  perusing  the  journals  is  formed,  the  ability  to 
discern  the  gold  among  the  dross  comes  rapidly. 
The  amount  of  actually  important  work  published 
is  but  a  small  fraction  of  the  total.  The  conception 
of  research  given  above  will  afford  an  unfailing 
touchstone  in  doubtful  cases. 

In  the  third  place,  students  seem  to  select  their 
universities  for  every  possible  reason  other  than  that 
certain  men  are  engaged  upon  certain  investigations 
there.  There  can  be  no  doubt  that  this  condition  is 
undesirable.  It  seems  to  be  due  to  a  lack  of  appre- 
ciation of  the  importance  and  meaning  of  research 
work,  as  well  as  to  ignorance  concerning  the  par- 
ticular activities  of  the  instructors.  To  a  certain 
extent  the  remedy  is  offered  herewith. 

Finally,  the  essays  which  make  up  this  volume 
may  be  regarded  as  a  small  contribution  to  the 
history  of  Science.  It  is  to  be  regretted  that  organic 
chemistry  is  commonly  regarded  as  a  labyrinthine 
specialty,  not  only  among  brother  scientists,  but 
among  brother  chemists  as  well,  s^rganic  chem- 
istry is  the  physiology  of  molecular  science.  No 
branch  of  human  activity  can  vie  with  its  rounded 
symmetry  and  completeness,  can  reduce  so  large  a 
percentage  of  its  facts  to  law  and  order,  or  can 
approach  nearer  to  the  ultimate  mystery  of  matter. 
And  so  the  study  of  systematic  progress  and  develop- 
ment which  it  offers  should  become  an  open  book  to 
every  man  of  science^ 

The  compilatioiToi  this  work  was  begun  in  Jan- 
uary, 1897,  at  Ann  Arbor,  and  completed  in  Octo- 


PREFACE  1* 

ber,  1898,  in  Eugene.  The  author  must  not  fail  to 
express  his  gratitude  to  Drs.  Freer  and  Sherman  of 
the  University  of  Michigan  and  to  Dr.  Solomons 
of  the  University  of  Wisconsin  for  their  patient  and 
vigorous  criticism  during  the  preparation  of  the 
greater  part  of  the  manuscript. 

ARTHUR  LACHMAN. 


EUGENE,  OREGON, 
October,  1898. 


CONTENTS 


PAGE 
V 


PREFACE     

INTRODUCTION xm 

CHAPTER  I 
THE  CONSTITUTION  OF  ROSANILINE         .... 

CHAPTER  II 
PERKIN'S  REACTION 12 

CHAPTER  III 
THE  CONSTITUTION  OF  BENZENE 21 

CHAPTER  IV  . 
THE  CONSTITUTION  OF  ACETOACETIC  ETHER.        .        •      60 

CHAPTER  V 
THE  URIC  ACID  GROUP 92 

CHAPTER  VI 
THE  CONSTITUTION  OF  THE  SUGARS        .        •        •        .    1H 

CHAPTER  VII 
THE  ISOMERISM  OF  MALEIC  AND  FUMARIC  ACIDS        .    154 


Xll  CONTENTS 

CHAPTER  VIII 

PAGE 
THE   ISOMERISM   OF    THE    OxiMES 170 

CHAPTER  IX 
THE  CONSTITUTION  OF  THE  DIAZO  COMPOUNDS  191 


AUTHOR  INDEX 223 

SUBJECT  INDEX  ...  225 


INTRODUCTION 

THE  GROWTH  OF  THE  SCIENCE  OF  ORGANIC  CHEMISTRY 

THE  magnificent  science  of  modern  Organic  Chem- 
istry, with  its  countless  compounds, — formed  of  but 
few  elements,  yet  varying  in  kaleidoscopic  array,  at 
one  time  showing  us  volatile  oils,  at  another  infu- 
sible solids,  embracing  brilliant-hued  dyes,  powerful 
poisons,  beneficent  medicines,  sweet  sugars,  and 
bitter  alkaloids,  contrasting  the  most  agreeable  with 
the  most  nauseating  odors ;  with  its  varying  reac- 
tions, dealing  at  one  time  with  acids,  at  another  with 
bases,  and  yet  again  with  neutral  substances;  with 
the  extreme  mutability  of  the  bodies  which  come 
within  its  realm,  —  fascinates  with  its  possibilities, 
while  it  appalls  with  its  vastness.  The  student 
stands  discouraged  at  the  very  threshold.  How  can 
he  ever  hope  to  master  the  general  classification,  let 
alone  the  minor  details,  which  must  become  a  part  of 
his  very  being,  if  he  too  wishes  to  do  his  share,  how- 
ever small,  toward  completing  and  rounding  out  the 
still  unfinished  structure  ?  The  answer  is  plain  :  he 
can  do  this  only  by  comprehending  the  spirit  of  the 
science,  by  learning  its  great  theories,  not  as  mere 
mnemonic  efforts,  but  as  the  result  of  a  development 
for  which  many  of  the  most  earnest  and  acute  minds 
known  to  the  history  of  science  have  fought  and 
toiled.  The  whole  subject  has  in  the  past  been  in  a 

xiii 


XIV  INTRODUCTION 

state  of  flux,  it  is  so  at  present,  and  its  point  of  con- 
gelation is  still  in  the  far  distant  future.  JpNone  of 
the  great  generalizations  of  to-day  have  come  to  us 
through  the  efforts  of  one  man ;  they  are,  on  the  con- 
trary, the  result  of  a  gradual  growth,  in  each  step  of 
which  the  mental  acumen  of  some  investigator,  per- 
haps long  since  dead,  can  be  seen,  and  each  great 
research  of  to-day  is  built  upon  some  perhaps  equally 
great  one  of  yesterday.  We  can  no  more  compre- 
hend the  present  structural  chemistry  without 
recalling  Berzelius,  Wohler,  Liebig,  Dumas,  Ger- 
hardt,  Kolbe,  or  Laurent,  than  we  can  the  Roman 
Empire  without  recognizing  the  part  played  in  its 
foundation  by  Caesar  and  Augustus^ 

When  in  1828  Wohler  demonstrated  the  forma- 
tion of  urea  from  ammonium  cyanate,  he  at  one  stroke 
broke  down  the  barrier  which  at  that  time  existed 
between  mineral  and  organic  chemistry.  Previously 
it  had  been  believed  that  all  substances  belonging  in 
the  domain  of  the  latter  were  of  necessity  the  prod- 
uct of  a  peculiar  "  vital  force,"  which  could  be  made 
subservient  to  man  only  in  so  far  as  he  might  himself 
be  able  to  construct  a  living  organism;  and  this  in 
itself,  with  the  given  hypothesis,  was  a  manifest 
impossibility.  Now  all  was  changed;  a  product  of 
vital  metabolism,  and,  indeed,  a  most  important  one, 
had  been  produced  in  the  laboratory,  and  from  so- 
called  inorganic  constituents.  Henceforth  the  two 
branches  of  the  science  were  to  travel  side  by  side, 
the  great  generalizations  of  the  one  aiding  in  the 
development  of  the  other,  until  now  it  can  truly  be 
said,  no  one  can  understand  the  spirit  of  inorganic 
without  being  thoroughly  conversant  with  that  of 


INTRODUCTION  XV 

organic  chemistry.  The  attention  of  chemists  was 
turned  from  purely  analytical  lines,  from  questions 
of  identification,  correlation,  and  classification  of 
mineral  substances  to  the  great  field  of  synthesis, 
involving  the  creation  of  multitudes  of  new  and 
interesting  substances.  The  expression  "nothing  is 
new  in  this  world"  cannot  surely  be  applied  to 
organic  chemistry,  for  in  this  chosen  field  of  so  many 
laborers  we  see  daily,  and  even  hourly,  new  indi- 
viduals brought  forth  and  christened  in  the  labora- 
tory, and  the  like  of  these  the  eye  of  man  never 
beheld  before. 

Although  this  new  field  of  science  can  point  to  an 
unbroken  record  of  progress  from  its  very  beginning, 
although  it  has  enriched  the  realm  of  human  knowl- 
edge with  many  and  important  discoveries,  it  has 
nevertheless  been  the  scene  of  most  persistent  strife, 
often  carried  on  with  an  acrimony  and  bitterness 
that  shocks  our  modern  sense  of  professional  cour- 
tesy. Its  triumphs  have  called  for  sacrifices  of 
human  lives  and  broken  hearts,  but  the  obstinacy  of 
past  conflicts  has  taught  us  to  respect  the  views 
of  others,  and  to  seek  for  a  verification  of  our  own, 
not  in  dogmatic  discussion,  but  in  careful  and  logical 
experimentation,  painstaking  in  the  minutest  detail, 
each  part  a  building  stone  from  which  the  final 
edifice  is  to  be  constructed.  Following  each  other 
in  rapid  succession,  there  arose  theory  after  theory, 
each  having  for  its  aim  the  explanation  of  the 
structure  of  the  organic  bodies  so  far  as  known;  each 
strong  in  that  it  was  founded  upon  some  experi- 
mental facts  ;  each  weak  in  that  it  could  not  embrace 
in  one  view  the  whole  of  the  field  it  sought  to  cover; 


xvi  INTRODUCTION 

each  in  turn  to  be  overthrown,  but  each  leaving  its 
germ  of  truth  to  be  utilized  by  its  successors.  First, 
greatest,  and  most  obstinately  maintained,  the  dual- 
istic  theory  of  Berzelius,  finally  giving  way  to  the 
substitution  doctrine  of  Gerhardt  and  Laurent ;  then 
the  radicle  theory  of  Liebig  and  Wohler,  subse- 
quently to  be  transformed  and  absorbed  by  the 
theory  of  types — all  views  finally  brought  into  con- 
tact at  once,  so  that  Laurent,  in  an  attempt  to  clear 
up  the  resulting  chaos,  sarcastically,  and  yet  rather 
sadly,  calls  attention  to  the  fact  that  for  such  a 
simple  substance  as  acetic  acid,  as  many  as  eleven 
different  structural  formulae  were  at  one  time  pro- 
posed.1 Indeed,  this  confusion  was  inevitable  so 
long  as  at  the  same  time  an  equal  confusion  reigned 
in  a  kindred  topic  of  the  science  —  the  determination 
of  atomic  weights.  Not  until  Cannizzaro,  by  his 
masterly  revival  of  Avogadro's  hypothesis,  taught 
chemists  to  use  a  consistent  and  logical  method  of 
determining  atomic  weights ;  not,  then,  until  investi- 
gators were  able  to  know  hotv  many  atoms  are 
included  in  each  molecule,  were  they  able  to  deter- 
mine properly  the  relative  positions  which  those 
atoms  bear  to  each  other  in  any  given  chemical  com- 
pound. From  the  remnants  of  the  past  conflicts 
much  has  been  taken.  The  dualistic  theory  of 
Berzelius  we  still  find,  shorn  of  its  dogma  and  its  in- 
flexibility, in  a  newer  and  more  reasonable  view  of  the 
influence  of  positive  and  negative  constituents  011 
the  character  of  chemical  compounds ;  Liebig's  and 
Wohler's  conception  of  compound  radicles,  however 

i  Laurent,  Chemical  Method,  p.  23. 


INTRODUCTION  xvil 

greatly  modified,  is  still  a  part  of  modern  chemistry; 
the  substitutions  of  Dumas  are  as  true  to-day  as  they 
were  fifty  years  ago — all,  however,  under  the  unify- 
ing influence  of  Cannizzaro's  revival,  are  brought 
into  one  great  stream  by  Williamson's  and  Kekule's 
theory  of  valence  and  of  structural  chemistry.  It  is 
this  advance  that  has  made  the  great  strides  of 
recent  years  possible ;  it  is  this  that  has  produced 
artificial  indigo  and  caffem,  cleared  up  the  dark 
mystery  of  the  sugar  group,  given  us  a  concise  and 
clear  understanding  of  the  derivatives  of  benzene 
and  of  the  terpenes,  made  possible  the  development 
of  the  aniline  and  azo-dye  industries,  enriched  medi- 
cine with  antipyrine,  phenacetine,  antifebrine,  and  in 
countless  ways  has  contributed  both  to  the  health 
and  the  happiness  of  mankind.  Mo-day  we  can 
scarcely  imagine  ourselves  without  these  adjuncts  of 
modern  civilization,  but  if  we  do  picture  to  ourselves 
what  the  world  would  be  were  we  deprived  of  them, 
we  must  give  all  credit  to  the  master  minds  that 
made  these  things  possible.  Truly,  in  no  other  field 
of  human  progress  can  it  be  said  with  equal  truth 
that  the  investigations  of  scientific  men,  working  for 
the  cause  of  science  alone  and  without  thought  of 
pecuniary  gain,  must  inevitably  have  preceded  the 
commercial  application  of  their  discoveries,  for  out 
of  the  chaos  of  the  past  have  sprung  the  industries 
of  the  present^ 

•No  student  of  organic  chemistry  can  afford  to 
neglect  the  historic  side  of  the  question ;  no  one  can 
claim  to  have  absorbed  its  spirit  unless  he  under- 
stands how  the  knowledge  of  the  present  has  grown 
from  the  toil  of  the  past,  and  none  may  expect  to 


xviii  INTRODUCTION 

create  for  himself  unless  he  understands  the  methods 
and  views  of  his  predecessors.  In  so  doing  he  must 
give  his  whole  soul  to  the  task  before  him<j-  Science 
is  a  stern  mistress,  who  gives  of  the  best  within  her 
only  to  those  who  follow  her  unflinchingly,  however 
difficult  the  task,  however  remote  the  prospect  of 
pecuniary  gain  or  of  self-aggrandizement,  their  sole 
hope  being  that  they  too  may  add  to  mankind's 
knowledge  of  truth,  so  that  future  generations  may 
profit  by  the  sacrifices  of  the  present^  This  has 
been  the  spirit  of  the  past ;  it  must  also  be  the  spirit 
of  the  present  and  of  the  future.  Science  is  moving 
onward,  swiftly,  relentlessly,  unflinchingly — no  half- 
hearted followers  for  her  —  the  weak  fall  by  the 
wayside,  there  is  no  place  for  those  who  have  not 
the  patience  to  acquire  the  necessary  knowledge,  the 
strong  press  forward  in  fierce  rivalry,  each  striving 
for  the  ultimate  goal  —  a  perfect  human  knowledge, 
by  which  from  any  given  premises  the  logical  conclu- 
sion may  be  drawn  with  unerring  accuracy.  Finis 
coronat  opus. 

PAUL  C.  FREER. 

ANN  ARBOR,  1899. 


THE  SPIRIT  OF  OEGANIC  CHEMISTEY 

O 

CHAPTER  I 

THE  CONSTITUTION  OF  ROSANILINE 

NOT  very  long  ago,  the  problem  of  determining  the 
constitution  of  rosaniline,  pararosaniline,  and  their 
derivatives  was  by  far  the  most  important  one  in  the 
whole  domain  of  technical  organic  chemistry.  In 
1857  W.  H.  Perkin  began  the  industrial  prepa- 
ration of  mauve,  the  first  so-called  "aniline-dye." 
The  phenomenal  success  attendant  upon  his  efforts 
roused  a  perfect  whirlwind  of  competitive  enthu- 
siasm. Everybody  who  could  devise  a  new  oxidizing 
agent  immediately  tried  it  on  aniline,  obtained  a  new 
dyestuff,  and  forthwith  patented  his  process.  Chief 
among  these  aniline  dyes  was  fuchsine,  the  storm- 
centre  itself.  In  France  a  tremendous  monopoly 
arose,  which  attempted  to  force  its  way  into  England 
and  Germany,  but  came  to  grief  thereby.  The 
struggles  of  its  competitors  called  forth  feverish 
activity  on  the  part  of  the  skilled  chemists  of  these 
countries ;  for  in  the  secret  of  the  exact  composition 
of  fuchsine  lay  the  method  for  its  most  successful 
preparation.  This  secret  was  completely  bared  in 
1878,  and  the  expected  results  were  not  long  in  arriv- 
ing. At  almost  the  same  moment,  however,  the 

1 


2  THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

commercial  importance  of  the  fuchsines  began  to 
wane,  for  the  azo-dyes  commenced  their  triumphant 
career,  and  to-day  have  largely  replaced  their  earlier 
competitors. 

It  is  to  A.  W.  Hofmann  that  we  owe  most  of  our 
knowledge  of  the  methods  for  preparing  fuchsine 
derivatives.  The  first  formula  assigned  to  the  mother- 
substance  was  C24H10N2O2.  Hofmann  showed  this 
to  be  wrong ;  the  fuchsine  base,  rosaniline,  is  repre- 
sented by  the  composition  C^H^NgO.1  The  aniline 
first  employed  in  the  manufacture  of  the  dyes  boiled 
between  180°-220° ;  manifestly  it  was  very  impure. 
With  the  progress  of  technical  skill  came  the  ability 
to  prepare  pure  aniline  ;  but  it  was  found  that  the 
oxidation  of  pure  aniline  gave  no  fuchsine  at  all. 
Hofmann  was  called  upon  to  investigate  this  curious 
result.  He  at  once  concluded  that  the  formation  of 
fuchsine  was  due  to  the  homologues  of  aniline,  which 
certainly  must  be  present  in  the  crude  product. 
Their  isolation  from  this  mixture  seemed  hopeless ; 
but  fortunately  Hofmann  possessed  a  small  quantity 
of  toluidine,  the  remnant  of  an  earlier  investigation 
on  toluene.  The  oxidation  of  toluidine,  however, 
gave  no  fuchsine.  It  was  not  until  he  oxidized  a 
mixture  of  aniline  and  toluidine  that  Hofmann2 
was  rewarded  by  a  most  brilliant  red  —  the  para- 
rosaniline  of  to-day.  Technically  the  problem  was 
solved ;  scientifically  it  received  a  great  impetus,  for 
the  mysterious  twenty  carbon  atoms  in  rosaniline 
were  seen  to  consist  of  six  from  the  aniline  and  twice 
seven  from  two  molecules  of  toluidine. 

1  Proc.  Roy.  Soc.  12,  2  (1862).  2  Ibid.  13,  490  (1864). 


THE  CONSTITUTION   OF  EOSANILINE  3 

Hofmann's  further  investigations  showed  that 
rosaniline  contained  replaceable  hydrogen  atoms; 
for  by  action  of  methyl  or  ethyl  iodides,  or  of  aniline, 
the  radicals  methyl,  ethyl,  and  phenyl  could  be 
introduced :  phenyl  three  times,1  the  others  six  times. 
This  led  him  to  the  conclusion  that  the  number  of 
replaceable  hydrogen  atoms  was  three;  the  hexa- 
methyl  and  ethyl  compounds  he  regarded  as  quater- 
nary ammonium  bases,  phenyl  not  forming  quaternary 
compounds.  Other  items  of  importance  for  the  deter- 
mination of  the  constitution  of  the  mother-substance 
were  also  discovered  by  Hofmann;  viz.  that  the 
salts  of  rosaniline,  the  actual  dyes,  contained  no 
oxygen,  but  were  derived  from  the  compound 
C20H19N3(C20H21N3O  -  H2O).  Reduction  of  the 
base  led  to  the  corresponding  Zewco-compound,2 
C20H21N3.  These  various  facts  led  him  to  consider 
rosaniline  as  a  triamine  with  three  free  hydrogen 
atoms.  Kekule3  expressed  this  conception  by  the 
following  formula : 

C6H4-NH-C6H3.CH3 
\  / 

NH       NH 
\/ 

C6H8.CH8 

This  formula  did  not  obtain  general  recognition ; 
from  occasional  footnotes  it  is  evident  that  Hofmann 
later  looked  upon  rosaniline  as  an  azo-compound ;  * 
and  this  latter  view  was  shared  by  many  others.  In 

1  Proc.  Boy.  Soc.  13,  6  (1863). 

2  Dyestuffs  are  very  frequently  easily  reducible  to  colorless 
substances  (Xeu/c6s,  white).     These  leuco-compounds,  in  turn,  are 
readily  oxidized  to  the  dyestuff ;  indigo  white  is  a  typical  example. 

3  Lehrbuch,  III,  672.       4  Ber.  d.  chem.  Gesell  5,  472  (1872). 


4:  THE  SPIBIT  OF  ORGANIC  CHEMISTRY 

addition,  certain  facts  did  not  agree  with  Kekule's 
formula.  Hofmann1  had  found  that  nitrous  acid 
acted  upon  rosaniline  with  formation  of  a  new  base. 
Caro  and  Wanklyn2  showed  this  base  to  be  a  diazo- 
compound ;  on  boiling  with  water  it  yielded  a  com- 
pound C20H16O3,  apparently  rosolic  acid.  It  now 
became  of  importance  to  settle  the  constitution  of 
rosolic  acid.  Caro  3  found  that  it  could  be  prepared 
by  a  process  exactly  analogous  to  that  employed 
with  rosaniline  ;  viz.  by  oxidation  of  a  mixture  of 
phenol  and  cresol,  i.e.  of  a  benzene  and  a  toluene 
derivative.  On  the  other  hand,  it  was  by  this  time 
well  established  by  various  investigators  that  rosolic 
acid  or  rosaniline  could  be  obtained  from  benzene 
derivatives  alone,  provided  oxalic  acid,  carbon  tetra- 
chloride,  or  other  simple  carbon  compounds  be 
present.  Evidently,  the  extra  carbon  atoms  of  the 
toluene  derivatives,  or  of  the  simple  compounds 
mentioned,  are  necessary  for  joining  the  benzene 
nuclei.  Taking  this  into  account,  as  well  as  the 
view  expressed  by  Hofmann  that  three  typical  hydro- 
gen atoms  are  present  in  the  molecule,  Caro  and 
Wanklyn  ascribed  the  following  formulae  to  rosani- 
line and  rosolic  acid : 


fNH.C6H6 


H 


[.C6H5 


O.C6H5 
O.C6H5 
O.C6H5 
H 


At   about   this   time   (1869),  Rosenstiehl4  found 
that  different  rosanilines  were  obtained  according  to 

1  Proc.  Hoy.  Soc.  12,  13  (1862).         2  Ibid.  15,  210  (1866). 

8  Ztschr.  Chem.  1866,  563. 

*  Jahresbericht,  1869,  693 ;  cf.  Ber.  d.  chem.  Gesell.  9,  441  (1876). 


• 
THE  CONSTITUTION   OF  ROSANILINE  5 

whether  ortho-  or  para-toluidine  were  employed  for 
the  purpose.  These  new  facts  did  not  collide  with 
the  then  current  theories,  however,  and  Rosenstiehl 
made  no  effort  to  capitalize  them.  This  was  reserved 
for  the  future. 

Caro  continued  his  researches  on  the  relation 
between  rosolic  acid  and  rosaniline,  and  in  1875  l 
showed  (in  conjunction  with  Graebe)  that  both  of 
these  substances  must  be  regarded  as  derivatives  of 
a  hydrocarbon  containing  twenty  carbon  atoms.  In 
many  respects  rosolic  acid  behaved  as  a  quinone  :  it 
added  various  bisulfites,  ammonia,  even  hydrochloric 
acid,  it  could  be  reduced  to  a  leuco-compound  ; 
with  acetic  anhydride  it  gave  a  triacetate.  These 
facts  Caro  and  Graebe  attempted  to  condense  into 
the  formula  : 


Rosaniline  was  given  the  analogous  constitution  : 

/•VTTT  \p  TT  ^  CH 
(NH2)C6H8  < 


These  formulae,  however,  failed  ta  account  for  the 
chief  series  of  reactions  connecting  the  two  com- 
pounds :  the  formation  of  a  diazo-compound  from 
rosaniline,  which  then  furnished  rosolic  acid.  Caro 
and  Graebe  fully  realized  this  discrepancy,  but  strad- 
dled it  with  the  lame  assumption  that  the  imido- 
groups  of  rosaniline  could  behave  like  amido-  groups 
towards  nitrous  acid. 

Similar  relationships  between  the  rosolic  acid  and 
rosaniline  compounds  had  been  discovered  by  Dale 

.  Chem.  (Liebig),  179,  184  (1876). 


6  THE  SPIRIT  OF  OEGANIC  CHEMISTRY 

arid  Schoiiemmer.1  But  just  at  this  time  Emil  and 
Otto  Fischer  2  had  accidentally  been  led  to  an  inves- 
tigation of  diazo-rosaniline ;  and  in  a  brief  space 3 
they  had  the  matter  pretty  definitely  cleared  up. 

By  applying  the  ordinary  reactions  for  the  com- 
plete elimination  of  the  diazo-complex  from  aro- 
matic compounds,  and  its  replacement  by  hydrogen, 
they  obtained  the  fundamental  hydrocarbon,  C20H18, 
of  which  rosaniline  is  the  derivative.  Considerable 
difficulty  was  experienced  in  determining  the  iden- 
tity of  this  hydrocarbon.  It  was  not  until  the 
hydrocarbons  resulting  from  the  supposedly  isomeric 
rosanilines  of  Rosenstiehl  were  investigated,  that 
the  question  was  settled.  Rosenstiehl  had  ascribed 
to  the  base  prepared  from  aniline  and  ortho-tolui- 
dine  the  name  rosaniline,  to  that  from  para-toluidine 
pseudo-rosaniline.  On  reducing  this  pseudo-rosani- 
line  to  the  leuco-base,  diazotizing,  and  boiling  with 
alcohol,  the  Fischers  obtained  a  hydrocarbon,  C19H16, 
which  proved  to  be  the  well-known  triphenylme- 
thane : 

HC.(C6H6)8 

The  hydrocarbon  obtained  from  technical  rosaniline, 
C20H18,  was  at  once  regarded  as  tolyl-diphenylme- 
thane,  and  the  supposition  clinched  by  experimental 
verification. 

Having  thus  by  analysis  ascertained  that  rosani- 
line (therefore  also  rosolic  acid)  is  a  derivative  of 
triphenylmethane  and  its  homologues,  the  Fischers 
proceeded  to  synthetically  prepare  rosaniline  com- 

1  J.  Chem.  Soc.  1873,  434 ;  1879,  148,  562. 

2  Ber.  d.  chem.  Gesell.  9,  891  (1876). 
*Ann.  Chem.  (Liebig),  194,  242  (1878). 


THE  CONSTITUTION  OF  ROSAN1LINE  1 

pounds  from  these  hydrocarbons.  First  a  word  con- 
cerning the  revision  of  nomenclature  necessitated  by 
these  researches.  Technical  rosaniline  and  rosolic 
acid  were  found  to  be  derived  from  tolyl-diphenyl- 
methane ;  in  view  of  the  practical  convenience  in 
preserving  these  designations,  it  was  decided  to  dis- 
tinguish the  lower  homologue  of  rosaniline  as  para- 
rosaniline,  to  recall  its  formation  from  aniline  and 
paratoluidine.  The  corresponding  rosolic  acid  (the 
triphenylmethane  derivative)  had  been  known  for 
some  time  as  "  Aurine  "  ;  this  name  was  retained. 

Triphenylmethane  is  readily  converted  into  trini- 
trotriphenylmethane.  Two  methods  lead  from  this 
substance  to  pararosaniline.  Direct  reduction  gives 
triamido-triphenylmethane,  or  leuco-pararosaniline  ; 
like  all  leuco-compounds,  this  is  converted  by  care- 
ful oxidation  into  the  dyestuff  pararosaniline  itself. 
The  second  method  proceeds  as  follows  :  trinitro-tri- 
phenylmethane  is  oxidized  to  the  corresponding  car- 
binol  by  chromic  acid  : 

HO.C(CeH4N02)8 

* 

Trinitro-triphenylcarbinol  is  reduced  by  zinc  dust 
and  acetic  acid  to  the  amido-compound,  pararosani- 
line. 

The  results  obtained  by  the  Fischers  may  be  sum- 
marized as  follows  : 

(1)  Leuco-pararosaniline  is  the  triamido-deriva- 
tive  of  triphenylmethane,  in  which  the  amido-groups 
are  evenly  distributed  among  the  three  benzene  nuclei. 
Its  formation  from  trinitro-triphenylmethane,  on  the 
one  hand,  and  from  paratoluidine  and  aniline,  on  the 
other,  show  this  conclusively. 


8  THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

(2)  Pararosaniline  and  its  leuco-compound  are  to 
each  other  as  triphenylcarbinol  is  to  triphenylme- 
thane  ;  this  is  shown  by  the  direct  formation  of  the 
dyestuff  from  the  trinitro-carbinol. 

This  would  lead  to  the  following  formula  : 


NH2.C6H4,        ,C6H 
NH2.C6H4/    \OH 

for  free  pararosaniline.  The  salts  of  this  base,  how- 
ever, do  not  contain  oxygen,  being  derived  from 
C19H17N3  (pararosaniline  less  water).  The  "color- 
base  "  would,  therefore,  probably  have  the  following 
constitution  : 


v        , 
NH2.C6H4/        m 

This  formula  explains  the  easy  addition  of  water,  as 
well  as  the  reduction  to  leuco-pararos  aniline,  It  also 
explains  a  much  older  reaction  of  the  rosanilines. 
Miiller1  had  shown  that  the  rosaniline  salts  add 
hydrocyanic  acid  to  form  very  stable  compounds, 
containing  three  amido-groups.  The  Fischers  as- 
cribe to  hydrocyanpararosaniline  the  constitution  : 

NH2.C6H4,        xC6H4.NH2 
NH2.C6H4/\CN 

The  position  of  the  amido-groups  in  the  benzene 
rings  still  remains  to  be  discussed.  An  observation  of 
Caro  and  Graebe's  2  determined  the  situation  of  two 
of  them.  Aurine,3  when  superheated  with  water, 

1  Ztschr.  Chem.  1866,  2. 

2  Ber.  d.  chem.  Gesell.  11,  1348  (1878). 
»  Cf  .  above. 


THE  CONSTITUTION   OF  EOSANILINE  9 

gives  p-dioxy-benzophenone,  therefore  contains  two 
of   its  hydroxyls  in  para  position  to  the   methane 

carbon  atom  : 

^C6H4OH  (p) 
CO 

(p) 


As  the  hydroxyls  of  aurine  correspond  to  the  amido- 
groups  of  pararosaniline,  two  of  the  latter  must  be 
in  para  position.  The  third  amido-group  is  also  in 
para  position.1  The  condensation  of  benzaldehyde 
with  aniline  to  form  cfo'amido-triphenylmethane  : 


C6H5  .  CHO  +  2  C6H5  .  NH2  =  C6H5  .  CH  <  '          +  H2O 


occurs  in  para  position,  since  by  first  converting  into 
the  dioxy-triphenylmethane  this  substance  also  yields 
p-dioxy-benzophenone.  Now  if  instead  of  benzalde- 
hyde p-nitro-benzaldehyde  be  employed  in  the  above 
reaction,  and  the  resulting  compound  reduced,  para- 
rosaniline is  the  final  product  ;  therefore  the  third 
amido-group  occupies  the  para  position. 

These  researches  of  E.  and  O.  Fischer  contained 
but  two  experimental  gaps,  which  have  since  been 
filled  in  by  E.  Fischer  and  Jennings.2  These  latter 
have  proved  that  pararosaniline  is  directly  converted 
into  triphenylcarbinol  by  the  diazo-reaction,  thus 
giving  the  reverse  of  that  process  whereby  triphenyl- 
carbinol is  converted  into  pararosaniline  by  nitration 
and  subsequent  reduction.  At  the  same  time  it  was 
also  shown  that  hydrocyanpararosaniline  has  the 
constitution  ascribed  to  it  above,  since  (by  means  of 

1  E.  and  0.  Fischer,  Ber.  d.  diem.  Gesell.  13,  2204  (1880). 

2  Ber.  d.  chem.  Gesell.  26,  2225  (1893). 


10          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

the   diazoreaction)  it   is   converted   into  triphenyl 

acetonitrile 

(C6H6)8C-CN 

and  therefore  contains  the  cyanogen  group  attached 
to  carbon. 

Of  late,  owing  to  the  curious  circumstance  that 
the  free  rosanilines  are  colorless,  whereas  their  salts, 
the  fuchsines,  are  intensely  colored,  speculation  has 
been  rife  as  to  the  cause  thereof.  These  have  been 
mostly  concerned  with  the  constitution  of  the  salts, 
though  very  recently  the  bases  themselves  have  been 
drawn  into  the  discussion.  Nietzki *  (1889)  assigned 
a  quinone-like  structure  to  the  fuchsines : 

>  C=C«H'=NH-HC1 

this  differed  but   little  from  the  one  proposed  by 
E.  and  O.  Fischer : 


viz.  by  just  the  difference  between  the  old  and  the 
new  quinone  formulae.  In  view  of  the  preference 
which  has  arisen  during  the  past  few  years  for 
quinone  formulae  for  colored  substances,  this  formula 
of  Nietzki  is  commonly  accepted.  Rosenstiehl2 
(1893),  indeed,  advanced  another  possibility  : 

(C6H4NH2)8C .  Cl 

regarding  fuchsine  as  a  hydrochloric  acid  ester,  and 
not  as  the  hydrochlorate  of  a  base.  But  Miolati3 

1  Chemie  der  organischen  Farbstoffe,  p.  117  (3d  ed.). 

2  Bull.  Soc.  [3],  9,  117  (1893). 

*  Ber.  d.  chem.  Gesell.  26,  1788  (1893). 


THE  CONSTITUTION   OF  EOSAN1LINE          11 

has  found  that  the  fuchsines  are  electrolytes,  and 
therefore  salts ;  this  excludes1  Rosenstiehl's  formula.2 
The  formula  of  pararosaniline  itself  has  been  some- 
what modified  by  Weil3  (1895).  Pararosaniline  is 
a  strong  base,  while  triamido-triphenylmethane  is 
a  very  weak  one.  If  both  of  these  compounds  have 
analogous  structures,  it  is  very  strange  that  the 
hydroxyl  derivative  should  be  much  the  more  basic 
of  the  two.  Weil  therefore  suggests  that  pararosani- 
line must  have  a  different  structure  than  its  mother- 
substance,  its  basic  properties  indicating  the  presence 
of  a  pentavalent  nitrogen  atom.  Of  the  various 
possibilities  which  incorporate  this  idea,  Weil's  ex- 
periments show  the  following  to  be  by  far  the  most 

probable : 

C  .  C6H4  .  NH8 


Further   details  have  been   promised,  and  will   be 
awaited  with  interest. 

The  history  of  rosaniline  has  been  comparatively 
free  from  complications,  one  single  research  having 
given  us  an  almost  complete  insight  into  its  consti- 
tution. The  pivotal  point,  of  course,  was  the  recog- 
nition of  triphenylmethane  as  the  backbone  of  the 
group.  The  method  here  exemplified,  of  building 
down  to  a  known  substance,  ascertaining  the  original 
structure  therefrom  by  induction,  and  verifying  this 
induction  by  synthesis  from  that  familiar  compound, 
typifies  the  mental  attitude  of  the  scientist  toward 
his  problems. 

1  Cf.  also  Fischer  and  Jennings,  I.e. 

*  Cf.  Rosenstiehl,  Bull.  Soc.  [3],  17,  373  (1897),  for  contradic- 
tory evidence.  8  Ber.  d.  chem.  Gesell  28,  205  (1895). 


CHAPTER   II 

PERKIN'S   REACTION 

THE  condensation  of  aromatic  aldehydes  with  salts 
of  aliphatic  acids,  commonly  known  as  Perkin's  reac- 
tion, has  had  a  very  curious  and  instructive  history. 
The  reaction  is  extremely  important  to  the  synthetic 
chemist,  and  has  contributed  in  no  small  degree  to 
our  knowledge  of  chemical  processes. 

In  1868,  W.  H.  Perkin1  described  a  synthesis  of 
coumarine,  consisting  in  the  action  of  acetic  anhy- 
dride on  the  sodium  salt  of  salicylic  aldehyde.  This 
choice  of  materials  was  determined  by  the  fact  that 
coumarine  is  decomposed  into  acetic  and  salicylic 
acids  on  fusion  with  caustic  alkalies.  Perkin  ex- 
plained this  reaction  as  follows :  The  first  step 
consists  in  the  formation  of  acetyl-salicylic  alde- 
hyde : 

C«H'  <  ONa  +  CHaCO  <  °  =  °^  <  O-COCH,  +  CHaCOONa 
The  aldehyde  then  loses  water  and  forms  coumarine  : 

/CHO  ^CO 

C6H4<  =  C6H8^  +  H20 

\0-COCH3  \COCH3 

1  J.  Chem.  Soc.  1868,  53  ;  Ann.  Chem.  (Liebig),  147,  229  (1868). 
12 


PERKIN'S  EEACTION  13 

The  reasons  which  led  Perkin  to  this  conclusion 
were : 

First.  Acetyl-salicylic  aldehyde  is  actually  formed 
when  the  reagents  employed  above  are  brought  to- 
gether in  cold  ether  solution. 

Second.  As  the  dehydration  is  caused  either  by 
the  excess  of  acetic  anhydride,  or  by  the  tempera- 
ture attained  (which  did  not  exceed  300°),  it  is  not 
likely  that  the  acetyl  group  is  involved,  especially 
as  acetic  acid  is  a  product  of  decomposition  (on 
fusing  with  alkalies). 

Third.  Coumarine  does  not  contain  an  acetyl 
group  attached  to  oxygen,  since  it  does  not  yield 
acetic  acid  on  treatment  with  aqueous  alkalies. 

Fourth.  Coumarine  contains  no  aldehyde  group, 
since  it  possesses  no  aldehyde  characteristics. 

However,  this  view  was  abandoned  shortly.  In 
the  first  place,  Perkin1  examined  the  behavior  of 
acetyl-salicylic  aldehyde,  and  found  that  it  could  not 
be  made  to  form  coumarine  unless  sodium  acetate 
be  present.  He  was  unable  to  explain  why.  And 
secondly,  the  coumarine  formula,  given  by  Perkin 
was  sharply  criticised  by  Fittig,2  who  pointed  out 
that  it  was  hardly  likely  for  the  benzene  ring  to 
give  up  hydrogen  in  such  a  nmn»€ri  and  that  inde- 
pendently of  this  the  formula  did  not  agree  with  the 
properties  of  coumarine  and  coumaric  acid.  Fittig 
recalled  a  reaction  discovered  by  Bertagnini3  and 
explained  by  Baeyer,4  in  which  cinnamic  acid  is 

1  J.  Chem.  Soc.  1868,  181 ;  Ann.  Chem.  (Liebig),  148,203  (1868). 

2  Ztschr.  Chem.  1868,  595  ;  Ann.  Chem.  (Liebig),  153,  358  (1870). 
9  Ann.  Chem.   (Liebig),  100,   125  (1856). 

*Ann.  Chem.   (Liebig),  Supp.  5,  81  (1867). 


14          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

formed  from  benzaldehyde  and  acetyl  chloride. 
Baeyer  showed  that  the  first  step  in  this  reaction  is 
a  condensation  : 

C6H6CHO  +  CH3COC1  =  C6H5CH=:CHCOC1  -f  H2O 

The  cinnamyl  chloride  subsequently  reacts  with 
water  : 

C6H5CH=CHCOC1  -f  H2O  =  C6H5CH=CHCOOH  +  HC1 

and  cinnamic  acid  is  the  result.  Fittig  offered  an 
analogous  explanation  of  Perkin's  reaction.  The 
aldehyde  group  condenses  with  half  of  the  acetic 
anhydride,  the  other  half  replaces  the  sodium  atom 
by  hydrogen  : 

ONa      CH3CO      o         p  H       OH  +  CH3COONa 
CHO  +  CH3CO  >  u  =  =  ^6^4  <  CH=CHCOOH 


The  resulting  product,  coumaric  acid,  loses  water  and 
forms  coumarine,  which  thus  becomes  the  anhydride 
of  oxycinnamic  acid  : 


/OH  ,O 

6H4<  =  C6H4<( 

XCH=CHCOOH  NCH= 


CHCO 

Perkin1  opposed  this  view  at  first;  he  could  not 
admit  that  coumarine  behaved  like  an  anhydride. 
However,  numerous  investigations  soon  proved  the 
correctness  of  Fittig's  formula,  and  Perkin  acknowl- 
edged himself  mistaken.  The  matter  rested  until 
187T,  when  Perkin2  prepared  cinnamic  acid  by  the 
action  of  acetic  anhydride  and  sodium  acetate  on 

i  J.  Chem.  Soc.  1869,  192.  2  Ibid.  1877,  338. 


PERKIN'S  REACTION  15 


benzaldehyde.  The  simplest  formulation  of  this 
reaction,  on  the  lines  of  Fittig's  explanation,  was 
the  following  : 

C6H6CHO  ,  CH3CO  .  n         C6H5CH=CHCOOH  ,  „  n 
C6H5CHO  +  CHaCO  >  °  =  =  C6H6CH=CHCOOH  + 

But,  unfortunately,  it  had  been  long  since  shown  by 
Geuther1  and  Huebner  2  that  benzaldehyde  and  acetic 
acid  form  not  cinnamic  acid,  but  benzylidene  diace- 
tate  : 


Once  more  sodium  acetate  is  found  to  play  a  mys- 
terious part  in  this  condensation.  Perkin's  3  attempts 
to  clear  matters  up  served  but  to  deepen  the  mystery. 
For  on  adding  to  the  mixture  of  benzaldehyde  and 
acetic  anhydride  sodium  butyrate  or  valerate  in  lieu 
of  the  acetate,  and  heating  to  180°  as  usual,  he 
obtained  cinnamic  acid  exclusively.  If,  however, 
sodium  propionate  and  propionic  anhydride,  or  sodium 
butyrate  and  butyric  anhydride,  were  employed  to- 
gether, homologues  of  cinnamic  acid  '  were  formed  ; 
viz.  phenylcrotonic  resp.  phenylangelic  acid.  To 
these  acids  Perkin  ascribed  the  formulae  : 

C6H6CH=CH-CH2-COOH,  Phenylcrotonic  acid 

C6H6CH=CH-CH2-CH2-COOH,  Phenylangelic  acid 

Succinic  anhydride  and  sodium  succinate  reacted 
with  benzaldehyde  with  evolution  of  carbon  diox- 
ide; a  substance  isomeric  with  phenylcrotonic  acid 

1  Ann.  Chem.  (Liebig),  106,  251  (1858). 

2  Ztschr.  Chem.  1867,  277.  8  I.e. 


16         THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

resulted,  which  was  called  isophenylcrotonic  acid. 
Perkin  expressed  this  reaction  thus : 


C6H6CHO  +|  \0  =  | 


CH2COX  C6H6CH=C-COOH 

CH2COOH 
C6H6CH=C-COOH 

=  I  +  coa 

CH8 

His  general  conclusions  were  that  in  all  cases  the 
salt  from  which  the  anhydride  is  derived  must  be 
present,  and  that  probably  the  carbon  atom  farthest 
removed  from  the  carboxyl  group  is  the  one  which 
condenses  with  the  aldehyde.  Of  this  latter  idea, 
however,  no  experimental  proof  was  offered. 

The  latter  tentative  hypothesis  soon  fell  before  a 
mass  of  contradictory  evidence.  Fittig l  showed  that 
unsaturated  acids  possess  a  double  bond  in  a-/3  posi- 
tion to  the  carboxyl  if  they  lose  carbon  dioxide  when 
treated  in  succession  with  hydrobromic  acid  and  an 
alkali.  All  of  Perkin's  acids  gave  this  reaction,  and 
therefore  belonged  in  the  category  of  aft  unsaturated 
compounds.  Baeyer  and  Jackson  2  proved  the  follow- 
ing structure  for  "phenylangelic  acid  : 

C6H6CH=:C-COOH 
CH2CH8 

And  finally,  Conrad  and  Bischoff 3  demonstrated  that 
Perkin's  formulae  for  phenylcrotonic  and  isophenyl- 
crotonic  acids  must  be  interchanged  : 

P~  i  Ann.  Chem.  (Liebig),  195,  169  (1879). 
2  Ber.  d.  chem.  Gesell.  13,  115  (1880). 
8  Ann.  Chem.  (Liebig),  204,  183  (1880). 


PERKIN'S  REACTION  17 

C6H6CH=C-COOH  Phenylcrotonic  acid 

CH3 
and  C6H6CH=CH-CH2COOH,    Isophenylcrotonic  acid 

This  much  was  certain,  then,  that  in  Perkin's  syn- 
thesis it  is  the  alpha  carbon  atom  which  reacts  with 
the  aldehyde.  The  part  played  by  the  salt  of  the 
acid,  the  presence  of  which  Perkin  had  found  to  be 
an  absolute  necessity,  was  cleared  up  soon  after  by 
two  incidental  observations  of  Fittig  and  Jayne,1 
during  the  course  of  the  investigation  on  unsaturated 
acids  already  referred  to.  In  the  first  place,  it  was 
found  that  in  the  synthesis  of  isophenylcrotonic  acid, 
succinic  anhydride  could  be  replaced  by  acetic  an- 
hydride with  great  advantage ;  also,  that  Perkin's 
working  temperature,  180°,  was  much  higher  than 
necessary,  100°  sufficing.  And  secondly,  working 
under  these  improved  conditions,  they  discovered 
that  the  first  product  of  the  reaction  is  a  new  sub- 
stance, viz.  phenylparaconic  acid  : 
C6H5CH-CH-COOH 

CH2 
O CO 

This  anhydride  loses  carbon  dioxide  on  heating  to 
150°,  and  passes  into  isophenylcrotonic  acid: 

C6H6CH-CH-COOH  C6H5CH=CH 

I  I 

CH2  =  CH2      +  CO2 

I  I 

O CO  COOH 

Three    conclusions    may   be    drawn    from    these 
unexpected    results.      Firstly,    condensation    occurs 

.  Chem.  (Liebig),  216,  100  (1883). 


18          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

between  the  aldehyde  and  the  sodium  salt;  the  an- 
hydride plays  merely  a  secondary  part.  Secondly, 
the  separation  of  water  is  preceded  by  an  addition 
process,  phenylparaconic  acid  being  the  anhydride 
or  lactone  of  phenylitamalic  (phenyloxypyrotartaric) 
acid : 

C6H5-CH(OH)  -CH-COOH 
I 
CH2COOH 

Thirdly,  the  separation  of  carbon  dioxide  is  also  a 
secondary  process. 

The  first  of  these  conclusions  was  in  direct  con- 
tradiction with  the  results  obtained  by  Perkin ;  as 
mentioned  above,  he  had  found  that  benzaldehyde 
and  acetic  anhydride  always  yielded  cinnamic  acid, 
no  matter  whether  sodium  acetate,  butyrate,  or  val- 
erate  was  employed.  But  experiments  carried  out 
by  Slocum,1  at  Fittig's  suggestion,  proved  that  Per- 
kin's  results  were  due  entirely  to  the  unnecessarily 
high  temperature  he  used;  for  if  the  temperature 
be  kept  not  much  above  100°,  acids  were  obtained 
corresponding  to  the  salt  taken,  irrespective  of  the 
anhydride  present.  Stuart,2  another  pupil  of  Fittig, 
showed  that  in  the  presence  of  acetic  anhydride  the 
salts  of  malonic  and  isosuccinic  acids  also  condense 
with  benzaldehyde  -,  these  acids  are  incapable  of 
forming  anhydrides. 

The  correctness  of  the  second  conclusion  was 
rendered  extremely  probable  by  various  cases  in 
which  lactonic  acids,  intramolecular  anhydrides  of 

1  Ber.  d.  Chem.  Gesell  16,  1436  (1883);  Ann.  Chem.  (Liebig), 
227,  55  (1885). 

2  J.  Chem.  Soc.  1883,  403. 


PERKIN'S  REACTION  19 

the  original  oxyacids,  result  from  the  reaction.  Di- 
rect addition  products  of  aldehydes  with  the  sodium 
salts  of  monobasic  acids  have  not  yet  been  obtained. 
In  one  case,  however,  Fittig,  together  with  Jayne1 
and  Ott,2  was  able  to  isolate  the  butyryl  derivative 
of  such  an  addition  product  (the  butyryl  derivative 
resulting  from  the  action  of  butyric  anhydride  on 
the  hydroxyl  group).  The  line  of  reasoning  fol- 
lowed ran  thus  :  If  the  reaction  really  consists  in 
the  union  of  aldehyde  oxygen  with  two  hydrogen 
atoms  of  the  salt,  with  direct  formation  of  an  unsatu- 
rated  acid  (or  its  salt),  then  such  acids  as  contain 
but  one  hydrogen  atom  attached  to  the  a-carbon 
atom  ought  not  to  react  with  aldehydes.  If,  on  the 
other  hand,  the  process  is  simply  one  of  addition, 
there  is  no  reason  why  such  an  acid  should  not  re- 
act. As  a  matter  of  fact,  Fittig  found  that  sodium 
isobutyrate,  treated  in  the  usual  manner,  yielded  the 
butyryl  compound  of  phenyloxypivalinic  acid  : 


C8H6CHO  +  H-C-COONa  =   C6H6CH(OH)C-COONa 


With  these  results,  the  history  of  Perkin's  reaction 
is  closed.  In  most  respects,  its  mechanism  has  been 
cleared  up,  so  that  it  constitutes  one  of  the  best- 
understood  chapters  of  organic  chemistry.  How- 
ever, its  own  history  has  shown  how  chary  we  must 
be  of  that  stamp  of  self  -approval,  Q.E.D.  Twice 
during  the  fifteen  years  here  recorded  did  it  seem  as 
if  all  dubious  points  had  been  settled.  Even  to-day, 

1  Ann.  Chem.  (Liebig)  ,  216,  115  (1883).      2  Ibid.  227,  119  (1885). 


20          THE  SPIEIT  OF  ORGANIC  CHEMISTRY 

with  all  the  insight  Fittig  has  given  us,  the  function 
of  the  acid  anhydride  is  as  uncertain  as  before.1 
Who  knows  but  that  another  revision  will  be  made 
necessary  when  further  results  come  home  ? 

1  Nef  explains  the  purpose  of  acetic  anhydride  in  this  reaction  as 
first  forming  benzylidene  diacetate.  Ann.  Chem.  (Liebig),  298,  309 
(1897).  It  is  too  early  to  assign  a  place  in  the  history  of  Perkin's 
reaction  to  this  view. 


CHAPTER  III 
THE  CONSTITUTION  OF  BENZENE 

FARADAY,  in  1825,  isolated  a  liquid  from  coal  gas, 
to  which  he  gave  the  name  "  bicarburetted  hydrogen." 
Nine  years  later,  Mitscherlich  found  that  the  same 
substance  was  obtained  by  the  dry  distillation  of 
benzoic  acid  with  lime.  These  famous  chemists 
little  thought  that  their  limpid  oil  would  once  lay 
claim  to  be  the  most  important  substance  in  organic 
chemistry,  that  it  would  give  birth  to  untold  thou- 
sands of  compounds,  that  it  would  revolutionize 
science  and  technology.1  The  technical  develop- 
ment of  benzene  and  its  derivatives  employs  over 
fifteen  thousand  workmen  in  Germany  alone  ;  the 
commercial  value  of  the  products  reaches  tens  of 
millions  of  dollars  ;  by  far  the  greater  portion  of 
the  research  work  done  to-day  is  concerned  with  the 
same  group  of  substances.  Nearly  all  of  this  tre- 
mendous activity  is  due  to  a  single  idea,  advanced 
in  a  masterly  treatise  by  August  Kekule  in  the  year 
1865.  Twenty-five  years  sufficed  for  the  chemists  of 
all  nations  to  recognize  the  inestimable  importance 
of  the  benzene  theory,  for  in  1890 2  they  came  to- 
gether at  Berlin  to  do  honor  to  the  man  who  had 
created  a  new  epoch  in  the  science. 

1  Interesting  details  are  given  by  H.  Caro,  Ber.  d.  chem.  Gesell. 
25,  Ref.  955  (1892). 

2  For  a  full  account  see  Ber.  d.  chem.  Gesell.  23,  1265  (1890). 

21 


22  THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Early  in  the  sixties,  organic  chemistry  was  just 
emerging  from  the  type  theory.  The  structural 
method  of  formulation  was  in  the  ascendant,  and 
mainly  through  the  efforts  of  Frankland,  William- 
son, Kekule,  Kolbe,  and  Butlerow,  the  genetic  rela- 
tions of  the  fatty  or  aliphatic  series  had  been  made 
clear.  In  contradistinction  to  these  compounds 
stood  a  group  of  "  aromatic "  substances,  not  as 
yet  very  numerous,  which  in  composition  and  be- 
havior differed  widely  from  the  former,  and  which 
seemed  to  form  a  marked  exception  to  the  laws  of 
valence  and  structure  laid  down  for  all  carbon  com- 
pounds. It  was  here  that  Kekule  surmounted  the 
difficulty.1 

"  In  attempting  to  give  an  account  of  the  atomic  constitution 
of  the  aromatic  compounds,  the  following  facts  must  be  taken 
into  consideration : 

"  (1)  All  aromatic  compounds,  even  the  simplest,  contain 
more  carbon,  comparatively  speaking,  than  analogous  com- 
pounds of  the  fatty  series. 

"  (2)  There  are  many  homologous  substances  in  the  aromatic 
series,  just  as  in  the  fatty ;  i.e.  substances  whose  difference  in 
composition  may  be  expressed  by  n  .  CH2. 

"  (3)  The  simplest  aromatic  compounds  contain  at  least  six 
atoms  of  carbon. 

"  (4)  All  products  derived  from  the  aromatic  compounds  pre- 
sent a  certain  family  resemblance ;  they  all  belong  to  the  group 
of  aromatic  substances.  A  portion  of  the  carbon  is  frequently 
eliminated  during  more  energetic  reactions,  but  the  chief  prod- 
ucts contain  at  least  six  atoms  of  carbon  (benzene,  quinone, 
chloranil,  phenol,  oxyphenic2  acid,  picric  acid,  etc.).  The  de- 

1  Bull.  Soc.   Chim.  3,   98  (1865);   Ann.   Chem.  (Liebig),  137, 
129  (1866);  Lehrbuch,  II,  493. 

2  The  old  name  for  pyrocatechol. 


THE  CONSTITUTION  OF  BENZENE  23 

composition  ceases  when  these  products  are  formed,  except 
when  complete  destruction  of  the  organic  molecule  takes 
place. 

"  These  facts  apparently  justify  the  conclusion  that  all  aro- 
matic substances  contain  one  and  the  same  group  of  atoms,  or, 
if  you  will,  a  common  nucleus  of  six  atoms  of  carbon.  Within 
this  nucleus  the  carbon  atoms  are  to  a  certain  extent  in  closer 
connection  or  conjunction.  Other  carbon  atoms  may  then  add 
themselves  to  this  nucleus,  in  the  same  manner  and  according 
to  the  same  laws  that  obtain  in  the  fatty  series. 

"  One  must  therefore  first  give  an  account  of  the  atomic  con- 
stitution of  this  nucleus.  ..." 

Kekule  then  proceeds  to  develop  his  now  classic 
views  on  the  constitution  of  benzene.  He  points 
out  that  the  six  carbon  atoms  are  probably  alter- 
nately connected  by  single  and  double  linkings,  to 
form  a  closed  chain  or  ring.  The  remainder  of  the 
treatise  is  devoted  to  a  detailed  consideration  of  the 
consequences  which  follow  from  this  conception. 
First,  the  constitution  of  many  of  the  better  known 
aromatic  substances  is  given ;  in  this  section  the 
principle  is  clearly  laid  down,  that  each  carbon  side- 
chain  is  converted  into  carboxyl  upon  oxidation  — 
to  this  day  one  of  our  most  important  diagnostic 
reactions. 

Kekule's  discussion  of  the  possibilities  of  isomerism 
is  extremely  interesting.  The  most  important  case 
is  where  the  substituents  are  located  in  the  benzene 
ring  itself.  Two  alternatives  presented  themselves  : 
either  all  six  of  the  hydrogen  atoms  are  equivalent, 
or  they  are  not.  Each  of  these  led  to  widely  differ- 
ent conclusions. 

I.  All  the  hydrogen  atoms  are  chemically  equivalent. 
If  so,  only  one  monosubstituted  benzene  can  exist, 


24          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

and  the  benzene  molecule  is  best  represented  by  a 
hexagon  : 


It  can  make  no  difference  whether  hydrogen  atom 
a  or  b,  or  any  other,  be  replaced  by,  e.g.,  bromine  ; 
the  compounds  are  identical : 


If  two  hydrogens  are  replaced,  the  theory  requires 
the  existence  of  three,  and  only  three,  disubstituted 
benzenes,  according  to  whether  the  positions  occupied 
are  db,  ac,  or  ad ;  for  position  ae  is  manifestly  iden- 
tical with  ac,  and  af  with  ab. 


If  three  atoms  of  hydrogen  are  substituted  by  the 
same  radical,  there  must  likewise  be  three  isomeric 
compounds  : 


THE  CONSTITUTION  OF  BENZENE  25 

whereas  if  one  of  the  three  sulDstituents  be  different 
from  the  other  two,  there  are  six  possibilities : 


II.    The  hydrogen  atoms  are  not  equivalent. 

"  The  six  hydrogen  atoms  form  three  groups,  each  consisting 
of  two  carbon  atoms  united  by  two  units  of  affinity  each.  The 
group,  therefore,  appears  as  a  triangle,  and  we  may  further  con- 
sider the  atoms  composing  it  so  arranged  that  three  atoms  of 
hydrogen  are  inside  the  triangle,  the  other  three  outside.  The 
six  hydrogen  atoms  are  then  alternately  unequal  in  value,  and 
benzene  may  be  represented  by  a  triangle.  Three  of  the  six 
hydrogens  are  located  at  the  angles  —  they  are  easily  accessible; 
the  other  three  are  at  the  middle  of  the  sides,  so  to  speak  in  the 
interior  of  the  molecule." 

Kekule  has  not  expressed  himself  very  clearly ; 
but  he  means  that  two  monosubstitution  products  of 
benzene  must  exist : 


and 


and  a  correspondingly  greater  number  of  di-  and  tri- 
derivatives. 

Kekule  inclined  to  the  first  view,  but  confessed 
himself  unable  to  prove  his  point.  He  proposed  to 
attack  the  problem  experimentally,  by  preparing  as 
large  a  number  as  possible  of  benzene  substitution 
products,  by  as  many  different  methods  as  possible, 


26          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

and  carefully  examining  them  with  regard  to  isom- 
erism.  By  means  of  purely  hypothetical  assump- 
tions, however,  he  made  an  attempt  to  determine  the 
constitution  of  the  di-brom-  and  brom-nitrobenzenes. 
These  deductions  were  shown  to  be  untenable  shortly 
afterward,  and  can  be  omitted  here. 

The  effect  of  this  treatise  of  Kekule's  was  electri- 
cal. In  part  or  in  their  entirety,  his  views  were 
adopted  by  almost  every  chemist  working  in  the 
field  of  aromatic  compounds.  A  vast  number  of 
experimental  researches  along  the  lines  laid  down  in 
this  brief  guide,  began  to  crowd  the  journals.  The 
development  was  in  three  directions,  along  each  of 
which  were  many  ups  and  downs.  The  literature  in 
question  is  enormous  in  extent ;  in  the  limited  scope 
of  this  book,  account  can  be  taken  only  of  the  work 
which  directly  contributed  to  the  advance  of  the 
subject.  The  three  lines  mentioned  are  as  follows  : 

(1)  The  equivalence  of  the  six  hydrogen  atoms, 
and  the   possible   number   of   isomeric   substitution 
products. 

(2)  The  genetic  relations  of  aromatic  compounds, 
with  reference  to  the  positions  occupied  by  the  sub- 
stituents. 

(3)  The   actual   distribution   of  the   six  valence 
units  which  the  simple  hexagonal  formula  does  not 
account  for. 

The  investigation  of  these  problems  proceeded  for 
the  most  part  simultaneously,  but  for  our  purposes 
it  will  be  best  to  treat  them  separately. 

This  epoch  in  the  history  of  chemistry  may  fitly 
be  compared  to  that  following  Dalton's  announce- 
ment of  the  atomic  theory.  A  very  limited  number 


THE  CONSTITUTION  OF  BENZENE  27 

of  facts  had  formed  the  basis  of  a  brilliant  and  com- 
prehensive generalization.  The  expectancy  of  the 
scientific  world  was  roused  to  the  highest  pitch,  and 
with  feverish  haste  and  activity  all  rushed  to  the 
chemical  Eldorado  to  participate  in  its  promised 
wealth  of  knowledge  and  insight.  A  similar  rush 
of  scientific  adventurers  occurred  three  years  ago, 
when  Roentgen  published  his  discovery  of  the  X- 
rays. 

I.  THE  RELATIONS  OF  THE  HYDROGEN  ATOMS 

At  the  time  when  Kekule  advanced  his  theory, 
and  expressed  the  opinion  that  only  one  form  of 
monosubstituted  benzene  exists,  there  were  two  sub- 
stances recorded  which  appeared  flatly  to  contradict 
this  assumption.  The  first  of  these  was  salylic  acid, 
prepared  by  Kolbe  by  reduction  of  salicylic  acid,  and 
found  by  him  to  be  isomeric  with  benzoic  acid. 
Kekule  expressed  his  conviction  that  salylic  acid  was 
nothing  other  than  impure  benzoic  acid ;  a  view 
which  was  experimentally  confirmed  by  Beilstein.1 
The  other  siibstance  was  a  second  .modification  of 
pentachlorbenzene,  prepared  by  Jungfleisch.  Kekule 
was  dubious  as  to  the  bona-fide  existence  of  this  com- 
pound, and  trusted  that  in  time  the  truth  would  be 
known.  Ladenburg2  (1874)  proved  that  only  one 
modification  of  pentachlorbenzene  exists,  the  sup- 
posed isomere  being  a  mixture  of  several  substances. 
Thus,  no  fact  is  known  which  contradicts  the  as- 
sumed equivalence  of  the  six  hydrogen  atoms  in 
benzene. 

1  Ann.  Chem.  (Liebig),  132,  151,  309  (1864). 

2  Ann.  Chem.  (Liebig),  172,  331  (1874). 


28          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Negative  arguments  are  not  convincing  or  satis- 
factory. And  so  Ladenburg  busied  himself  to  find 
positive  proof  of  Kekule's  proposition.  He  was  able 
to  show,1  from  the  various  formations  of  thymoqui- 
none,  that  in  benzene  two  pairs  of  hydrogen  atoms 
are  symmetrically  situated  with  reference  to  one  of 
the  remaining  atoms.  This,  historically  the  first 
proof,  is  of  rather  a  complicated  nature,  and  not 
easily  followed  ;  as  several  very  much  clearer  dem- 
onstrations of  the  theorem  have  been  given,  it  can 
be  safely  omitted  in  detail. 

The  existence  of  one  pair  of  symmetrical  hydrogen 
atoms  had  been  shown  considerably  earlier  by  Hueb- 
ner  and  Petermann2  (1869).  Brombenzoic  acid 
yields  two  nitrobrombenzoic  acids.  If  these  are  re- 
duced to  the  amido  acids  (which  are  still  different), 
and  then  by  further  reduction  the  bromine  elimi- 
nated, the  resulting  amidobenzoic  acids  are  identical. 
Now  in  the  nitrobrom-  (and  amido-)  brombenzoic 
acids,  the  difference  in  properties  must  be  caused  by 
differences  in  position  of  the  nitro  (and  amido) 
groups.  As,  however,  by  removal  of  the  bromine 
atom  only  one  amidobenzoic  acid  is  obtained  from 
two  substances,  the  amido  (and  nitro)  groups  in 
these  latter  must  be  symmetrically  situated  with 
respect  to  the  carboxyl  group,  as  otherwise  the  final 
products  could  not  be  identical. 

The  best  proof  by  far  of  the  existence  of  two  sym- 
metrical pairs  of  atoms  in  the  benzene  ring  was  given 


p.  344,  Theorie  der  arom.  Verbindnngen,  p.  14  (1874); 
Ladenburg  and  Engelbrecht,  Ber.  d.  chem.  G-esell.  10,  1218  (1878). 
2  Ann.  Chem.  (Liobig),  149,  130  (1869)  ;  cf.  Ladenburg,  Ber.  d. 
chem.  Gesell.  2,  140  (1869),  for  this  explanation. 


THE  CONSTITUTION  OF  BENZENE  29 

by  E.  Wroblewsky,1  in  1878.  Wroblewsky  prepared 
all  five  possible  brom-benzoic  acids,  in  order  to  see 
how  many  are  identical.  The  chart  on  page  31 
will  serve  to  illustrate  the  reactions  which  he  em- 
ployed for  this  purpose.  His  starting-point  was 
a  brom-toluidine  (I).  By  eliminating  the  amido 
group  by  means  of  the  diazo  reaction,  a  brom- 
toluene  (II)  results,  which  upon  oxidation  gives 
meta-brombenzoic  acid  (III).  This  concludes  one 
series  with  a  well-known  compound.  Starting  again 
with  brom-toluidine  (I),  nitration  (IV)  with  sub- 
sequent elimination  of  the  amido  group  gives  a 
nitro-brom-toluene  (V),  which  is  reduced  to  another 
brom-amido-toluene  (VI).  Further  reduction  re- 
moves the  bromine  (VII)  ;  the  resulting  meta- 
toluidine  is  diazotized,  the  diazo  group  replaced 
by  bromine,  and  we  have  a  brom-toluene  (VIII) 
identical  with  II,  which  is  oxidized  to  a  brom-ben- 
zoic acid  (IX)  identical  with  III.  Position  1-3 
is  therefore  equivalent  to  position  1-5,  and  hydro- 
gen atoms  3  and  5  form  a  symmetrical  pair  with 
respect  to  hydrogen  atom  1.  Wroblewsky's  third 
series  again  commences  with  compound  I.  Pre- 
paring IV  as  above,  the  amido  group  is  exchanged 
for  an  iodine  atom  by  means  of  the  diazo  reaction 
(X).  Reduction  of  this  new  substance  gives  a 
brom-iodo-toluidine  (XI),  whose  amido  group  is 
likewise  exchanged  for  a  bromine  atom  (XII).  We 
now  have  a  toluene  with  three  substituents,  leaving 
only  two  vacant  places  in  the  ring  open  for  attack. 
Nitration  forces  a  nitro  group  into  one  of  these  two 


Chem.  (Liebig),  192,  196  (1878). 


30  THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

places  (it  makes  no  difference  which  one  we  assume 
to  be  thus  occupied).  The  dibrom-iodo-nitro-toluene 
(XIII)  thus  obtained  is  reduced  to  the  corresponding 
toluidine  (XIV),  further  reduction  removing  all  the 
halogen  atoms  and  leaving  ortho-toluidine  (XV). 
This  is  now  converted  into  brom-toluene  (diazo-re- 
action)  (XVI),  and  finally  oxidized  to  ortho-brom- 
benzoic  acid  (XVII).  Thus  we  have  established  the 
formula  of  a  third  brom-benzoic  acid.  The  fourth 
series  begins  with  compound  XIV.  By  means  of 
the  diazo  reaction,  the  amido  group  is  replaced 
by  iodine  (XVIII).  The  resulting  dibrom-diiodo- 
toluene  possesses  but  one  replaceable  hydrogen  atom, 
the  one  which  in  XIII  was  not  attacked  ly  nitric  acid. 
This  last  hydrogen  is  exchanged  for  the  nitro  group 
(XIX),  reduction  yields  an  amine  (XX),  and  ener- 
getic treatment  with  nascent  hydrogen  removes  all 
of  the  halogen  atoms.  The  product  is  ortho-tolui- 
dine (XXI),  identical  with  (XV).  The  brom- 
toluene  (XXII)  and  brom-benzoic  acid  (XXIII) 
which  it  gives,  are  of  course  identical  with  the  sub- 
stances XVI  and  XVII,  and  thus  our  fourth  brom- 
benzoic  acid  is  one  and  the  same  with  the  third, 
thereby  establishing  the  existence  of  a  second  sym- 
metrical pair  of  hydrogen  atoms.  As  to  the  fifth 
brom-benzoic  acid,  it  is  readily  prepared  from  para- 
toluidine  by  reactions  similar  to  the  pnes  just  dis- 
cussed, and  is  different  from  either  of  the  other  two 
(or  four). 

This  important  demonstration  thus  clearly  proves 
the  existence  of  the  symmetry  postulated  by  Kekule, 
and  further  shows  that  three,  and  only  three,  di- 
substitution  products  of  benzene  can  exist.  A  year 


THE  CONSTITUTION  OF  BENZENE 


31 


later,  it  was  supplemented  by  Huebner,1  who  com- 
pleted his  previous  work  by  illustrating  a  second 
pair  of  correlated  hydrogen  atoms.  Salicylic  acid 


CH, 


CH 


coon 


gives  two  nitro  derivatives.     These  nitro-hydroxy- 
benzoic  acids  are  converted  into  nitro-amido-benzoic 

i  Ann.  Chem.  (Liebig),  195,  1  (1879). 


32          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

acids  upon  boiling  with  ammonia.  These  two  acids, 
when  the  amido  group  is  removed  (diazo  reaction), 
give  one  and  the  same  nitro-benzoic  acid.  Therefore 
they  contain  nitro  groups  symmetrically  arranged 
with  reference  to  the  carboxyl  group.  This  nitro 
acid  reduces  to  an  amido-benzoic  acid  different  from 
the  one  Huebner  obtained  previously,  and  the  two 
nitro  groups  thus  correspond  to  a  symmetrical  pair 
of  hydrogens  differing  from  the  previous  pair. 

Upon  the  basis  of  what  is  thus  proved,  viz.  that 
only  three  di-substituted  benzenes  can  exist, 

ab  =  af,  ac  =  ae,  and  ad, 

Ladenburg l  was  able  to  show  the  equivalence  of  all 
six  hydrogen  atoms  in  benzene.  Phenol  passes  into 
brom-benzene  when  treated  with  phosphorus  penta- 
bromide  ;  and  brom-benzene  is  converted  into  ben- 
zoic  acid  when  treated  with  carbon  dioxide  and 
sodium.  We  thus  pass  from  phenol  to  benzoic 
acid,  and  if  the  idea  of  definite  positions  in  the 
ring  has  any  meaning  at  all,  the  hydroxyl  of  the 
one  must  occupy  the  same  place  as  the  carboxyl  of 
the  other.  We  may  call  this  position  a.  Now 
three  (^6xy-benzoic  acids  are  known.  These  may 
all  be  reduced  to  ordinary  benzoic  acid,  and  there- 
fore they  contain  their  carboxyl  group  in  position  a. 
The  hydroxyl  groups  must  be  in  three  different 
positions,  as  the  acids  are  different ;  these  may  be 
designated  as  b,  c,  and  d.  When  the  oxybenzoic 
acids  are  heated  with  lime,  carbon  dioxide  is  split 
off,  and  phenols  result  which  must  contain  their 

lBer.  d.  chem.  Gesell.  7,  1684  (1874). 


THE  CONSTITUTION  OF  BENZENE  33 

hydroxyl  respectively  in  positions  b,  c,  and  d. 
These  phenols  were  found  to  be  identical  with 
ordinary  phenol,  which  contains  hydroxyl  in  a. 
Therefore  it  makes  no  difference  whether  a  mono- 
substituted  benzene  contains  the  substituent  in  a, 
b,  c,  or  d  ;  the  compounds  are  identical,  and  these 
positions  must  be  absolutely  equivalent.  Among 
the  three  hydrogens  b,  c,  and  d,  no  two  are  sym- 
metrical towards  a,  for  the  three  oxybenzoic  acids 
could  not  then  be  different  from  one  another.  The 
remaining  atoms  e  and  f  must  be  situated  with 
regard  to  a  just  as  two  of  the  atoms  b,  c,  and  d. 
The  oxybenzoic  acids 


C6H4(C02H)(OH)    and 


aH)  (Oil) 


must  be  identical  with  two  of  the  known  oxybenzoic 
acids,1  and  the  phenols  resulting  from  them 

C6H6(OH)    and    C6H6(OH) 

identical  with  ordinary  phenol.  Therefore  all  six 
positions  in  the  benzene  ring  are  equivalent  ;  no 
matter  which  of  them  is  substituted  by  a  radical, 
the  resulting  compound  is  the  same. 


II.     THE   GENETIC  RELATIONS  OF  AKOMATIC 
COMPOUNDS 

Kekule  made  an  attempt  to  determine  the  location 
of  substituents  by  deduction  from  unfounded  general 
principles.  It  was  found  later  that  no  general  prin- 
ciples obtained  here,  that  the  problem  was  essentially 

1  This  follows  from  Wroblewsky's  work. 


34          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

experimental  in  its  nature.  Koerner,  a  pupil  of 
Kekule's,  proposed  to  distinguish  the  three  series  of 
isomeric  compounds  by  the  prefixes  still  in  use,  ortho, 
para,  and  meta.  At  first  there  was  great  confusion, 
until  Kekule  suggested  that  all  compounds  which 
were  shown  to  be  related  to  a  standard  ortho  com- 
pound should  be  called  ortho,  etc.  These  group 
names  were  in  use  for  a  long  while  before  it  was 
known  to  what  actual  differences  in  position  these 
designations  corresponded.  Later  it  was  found  that 
most  of  the  substances  termed  para  contained  their 
substituents  in  the  1-4  position,  and  therefore  this 
prefix  was  adopted  for  such  substances  only.  The 
same  may  be  said  of  the  ortho  and  meta  compounds. 
It  required  over  ten  years  of  incessant  labor  on 
the  part  of  Koerner,  V.  Meyer,  Griess,  Ladenburg, 
and  many  others  to  finally  establish  fixed  standards 
of  reference  and  fit  all  aromatic  compounds  to  them. 
The  first  step  was  taken  by  Baeyer1  (1868),  who 
remarked  that  the  formation  of  mesitylene  from  ace- 
tone was  best  explained  by  assuming  a  symmetrical 
structure  for  the  former ;  and  as  Fittig  had  shown 
mesitylene  to  be  trimethyl  benzene,  its  formula  could 

be  written : 

CHS 


CHS« 


A  few  years  later  (1869)  Graebe2  found  that  naphtha- 
lene was  to  be  represented  by  the  following  formula: 

i-Ann.  Chem.  (Liebig),  140,  306  (1866). 
149,  1  (1869). 


THE  CONSTITUTION  OF  BENZENE  35 


As  naphthalene  on  oxidation  furnished  phthalic  acid, 
the  constitution  of  the  latter  was  thus  fixed  as 
1-2  (ortho) : 


the  formula  still  given  to  it.  At  about  the  same 
time  Ladenburg1  pointed  out  that  para  compounds 
must  have  the  position  1-4;  this  left  1-3  for  the 
meta  compounds. 

All  this  seemed  simple  enough ;  substances  which 
can  be  converted  into  phthalic  acid  belong  to  the 
ortho  series,  containing  their  substituents  in  1-2 
position ;  etc.  The  trouble  lay  in  the  fact  that  the 
reactions  selected  to  show  genetic  relations  were 
frequently  absolutely  unreliable.  Considerable  dif- 
ferences of  opinion  obtained  until  a  sufficiently  large 
number  of  facts  had  been  amassed  to  weed  out  the 
disturbing  irregularities.  For  the  sake  of  the  interest 
attaching  to  these  erroneous  views,  a  short  list  of 
them  will  be  given. 

Graebe2  considered  hydroquinone  and  metaoxy- 
benzoic  acid  to  be  ortho  compounds,  in  the  same 
series  with  phthalic  acid :  salicylic  acid  and  pyrocate- 
chol  as  meta,  resorcinol  as  para.  Huebner  and  Peter- 
mann3  regarded  ordinary  brombenzoic  acid  (meta)  as 

i  Ber.  d.  chem.  Gesell  2,  140  (1869).          «  z.c.          s  j.c. 


36          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

belonging  in  the  same  category  with  salicylic  acid, 
which  was  therefore  also  meta ;  as  anthranilic  acid 
is  directly  convertible  into  salicylic  acid,  it  also  was 
a  meta  compound.  As  late  as  1871,  V.  Meyer l 
adopted  the  classification  of  the  dioxybenzenes  given 
by  Graebe ;  quinone,  resulting  from  hydroquinone 
by  simple  oxidation,  must  likewise  be  ortho.  In 
the  same  paper,  dinitrobenzene  (meta)  is  regarded 
as  1-4,  volatile  nitrophenol  (ortho)  as  1-3,  non- 
volatile nitrophenol  (para)  as  1-2.  Salicylic  acid 
is  shown  to  be  an  ortho  compound.  The  following 
year  Salkowsky  and  Zincke2  independently  showed 
that  the  volatile  nitrophenol  belongs  to  the  ortho 
series.  In  1873  Huebner  and  Schneider3  agreed 
with  this  view,  and  suggested  that  the  non-volatile 
compound  is  1-4.  These  authors  are  still  uncertain 
as  to  the  exact  relations  of  the  dioxybenzenes.  Dur- 
ing the  same  year  Wroblewsky 4  clearly  showed  the 
relations  between  a  large  number  of  disubstituted 
products.  V.  Meyer5  (1874)  says  that  dinitro- 
benzene and  resorcine  are  members  of  the  same  series 
(according  to  Koerner),  and  that  resorcine  is  un- 
doubtedly connected  with  terephthalic  acid  ;  there- 
fore dinitrobenzene  and  resorcine  must  be  para 
compounds.  Quinone,  he  says,  is  now  universally 
conceded  to  be  1-3.6  Pyrocatechol  is  shown  to  be 
an  ortho  derivative. 


1  Ann.  Chem.  (Liebig),  159,  21  (1871). 

2  Ber.  d.  chem.  Gesell.  5,  114,  874  (1872);  ibid.  6, 123, 140  (1873). 

3  Ann.  Chem.  (Liebig),  167,  114  (1873). 
*Ann.  Chem.  (Liebig),  168,  147  (1873). 
'  Ann.  Chem.  (Liebig),  171,  57  (1874). 

« Cf .  above. 


THE  CONSTITUTION  OF  BENZENE  37 

These  few  examples  will  suffice  to  show  in  how 
unsettled  a  condition  the  problem  remained  for  a 
long  period.  The  chief  cause  thereof  was  that  re- 
arrangements took  place  during  the  reactions  relied 
upon  to  give  a  clear  genealogy,  so  that  the  substitu- 
ents  after  reaction  were  no  longer  in  the  same  relative 
positions  as  before.  For  instance,  all  three  phenol 
sulfonic  acids1  were  found  to  give  the  same  dioxy- 
benzene  on  fusion  with  alkalies,  viz.  resorcinol.  The 
action  of  potassium  cyanide  on  bromnitro  compounds, 
a  reaction  largely  relied  upon  to  furnish  substituted 
benzoic  acids,  was  shown  to  be  accompanied  by  similar 
rearrangements,2  so  that  the  material  gathered  in  this 
way  was  quite  unavailable  for  the  purpose  in  question. 

An  exact  and  thoroughly  reliable  basis  for  the  deter- 
mination of  the  constitution  of  aromatic  compounds  was 
furnished  by  Koerner?  Grriess,*  and  Salkowskif  inde- 
pendently of  one  another.  This  consisted  in  showing 
what  the  relations  are,  and  must  be,  which  obtain  be- 
tween di-  and  tri-substituted  benzenes.  Suppose  that 
the  di-derivatives  of  the  formula  C6H4X2  are  con- 
verted into  tri-derivatives  C6H3X2Y  ;  where  Y  may 
be  identical  with  X,  or  different  from  it.  It  is  clear 
that  an  ortho  compound  will  give  two  tri-derivatives  : 


and 


1  Cf.  Kekute,  Ber.  d.  chem.  Gesell.  2,  330  (1869). 

2  V.  Bichter,  Ber.  d.  chem.  Gesell.  8,  1418  (1875). 
8  Gazz.  Chim.  ital.  4,  443  (1875). 

*  Ber.  d.  chem.  Gesell  7,  1226  (1874). 

*  Ann.  Chem.  (Liebig),  173,  66  (1874). 


38          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Similarly,  a  meta  compound  will  give  three : 
x  xx  x 


The  para  compounds  can  yield  only  one  : 
x  x 


Koerner  used  the  dibrombenzenes  to  illustrate  this 
principle.  He  found  that  the  dibrpmbenzene  boiling 
at  220°  gave  three  tribrom-  and  three  nitrodibrom- 
benzenes,  and  must  therefore  be  the  meta  compound. 
Another  dibrombenzene  (melting  at  —  1°  and  boiling 
at  224°)  gave  two  nitro  derivatives  and  two  tribrom 
compounds,  and  is  thus  the  ortho  member.  The  third 
dibrombenzene  must  therefore  be  the  para  compound ; 
it  in  fact  furnished  only  one  nitro  product  and  one 
tribrombenzene.  Griess  and  Salkowski  employed  the 
relations  between  the  six  isomeric  diamidobenzoic 
acids  and  the  three  diamidobenzenes.  On  splitting 
off  carbon  dioxide  from  the  acids,  three  gave  a  phenyl- 
endiamine  melting  at  62°,  two  a  diamine  melting  at 
102°,  one  a  diamine  melting  at  140°.  The  first-men- 
tioned diamidobenzene  is  therefore  a  meta,  the  second 
an  ortho,  the  third  a  para  compound. 

A  number  of  other  investigations  on  this  problem 
of  the  constitution  of  benzene  derivatives  have  been 
published,  of  which  only  one  more  need  be  considered 


THE  CONSTITUTION  OF  BENZENE  39 

here.  This  is  Ladenburg's1  proof  of  the  equivalence 
of  the  three  non-substituted  hydrogen  atoms  in  mesi- 
tylene  (thus  showing  its  symmetrical  structure). 
On  nitrating  the  hydrocarbon  a  dinitro  product  is 
obtained  ;  the  nitro  groups  may  be  considered  in 
positions  a  and  /S ;  by  reduction  of  one  of  the  nitro 
groups  (let  us  say  /3),  a  nitromesidine  is  obtained  : 

C6(CH3)8(N02)(NH2)(H). 

If  the  amino  group  be  acetylated,  a  further  nitro 
group  may  be  introduced  (by  direct  nitration): 

C6(CH3)3(N02)(NH .  C2H30)(NS2). 
When  this  dinitroacetmesidine  has  its  —  NH .  C9HoO 

/       o 

group  replaced  by  hydrogen  (by  first  saponifying 
the  acetyl  group  and  then  eliminating  the  amino 
group  by  means  of  the  diazo  reaction),  a  dinitrome- 
sitylene  is  obtained  : 

C6(CH3)3(N02)(H)(N#2), 

which  is  identical  with  the  original  dinitromesi- 
tylene  : 

C6(CH3)8(N02)(N02)(H). 

Therefore  hydrogen  atoms  /3  and  7  are  equivalent. 
If,  further,  in  the  above-mentioned  nitromesidine, 

C6(CH3)3(N02)(NH2)(H), 

the  amido  group  be  eliminated  (by  means  of  the 
diazo  reaction),  the  nitro  group  then  reduced  to 

lAnn.  Chem.  (Liebig),  179,  174  (1875). 


40          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

amino  arid  this  acetylated,  there  results  an  acetme- 
sidine  : 

C6(CH8)3(NH .  C2H80)(H)(H). 

When  this  is  nitrated,  the  entering  nitro  group  must 
be  either  in  position  y8  or  7 : 

C6(CH8)3(NH .  C2H80)  (N02)  (H) 

or  C6(CH3)8(NH  .  C2H3O)  (H)  (N32). 

But  these  formulse  are  identical,  since,  as  just  shown, 
positions  y8  and  7  are  equivalent.  If  from  this  nitro- 
acetmesidine  the  acetyl  group  be  removed,  there 
results  a  nitromesidine  : 

C6(CH3)3(NH2)(N02)(H), 

which  proves  to  be  identical  with  the  nitromesidine 
taken  as  a  starting-point  : 

C6(CH3)3(N02)(NH2)(H). 

Therefore  atom  a  is  likewise  equivalent  with  atom  /:?, 
and  mesitylene  has  the  symmetrical  structure  : 


CH 


All  subsequent  work  has  been  based  on  the  rigid 
foundation  furnished  by  these  investigations.  The 
problem  of  determining  the  structure  of  benzene 
compounds  of  course  comes  up  with  every  new  sub- 
stance discovered.  Many  more  complicated  aromatic 
compounds  still  await  their  complete  identification, 
which  can  only  be  a  question  of  time  and  diligence. 


THE  CONSTITUTION   OF  BENZENE  41 

III.    THE  DISTRIBUTION  OF  VALENCES  IN  THE 
BENZENE   RING 

We  have  seen  that  the  comparatively  short  period 
of  ten  years  sufficed  abundantly  to  confirm  the  views 
of  Kekule  as  regards  symmetry  of  the  benzene  ring, 
and  the  consequences  resulting  therefrom.  Not  so 
with  the  actual  structure  proposed  by  him  at  the 
same  time.  Kekule's  original  formula,  it  will  be 
remembered,  was  based  on  the  assumption  that  the 
six  carbon  atoms  were  united  by  single  and  double 
linkings  alternately : 


It  is  not  to  be  supposed  that  at  that  time  Kekule 
considered  his  formula  to  be  a  complete  and  thorough 
diagrammatic  representation  of  all  the  properties  of 
the  benzene  complex.  The  formula  was  merely  the 
simplest  expression  thereof,  under  existing  circum- 
stances. Until  the  more  pressing  question  of  sym- 
metry was  definitely  settled,  that  of  structural  detail 
was  of  a  nature  more  suitable  to  interest  debating 
societies  than  to  occupy  the  thoughts  and  direct  the 
efforts  of  earnest  scientists. 

However,  it  did  not  escape  the  watchful  eyes  of 
his  contemporaries  that  Kekule's  own  formula  pre- 
cluded some  of  the  consequences  he  deduced  from 
it :  it  admits  of  two  isomeric  ortho  derivatives : 


42          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Kekule  was  therefore  compelled  to  issue  an  addi- 
tional hypothesis1  in  aid  of  his  main  theory  (1872). 
This  hypothesis  was  as  follows  :  If  we  suppose  the 
atoms  to  be  in  continual  motion,  striking  against 
one  another  as  they  vibrate,  then  the  difference 
between  a  single  and  a  double  linking  among  the 
carbon  atoms  may  be  easily  imagined  to  lie  in  that 
the  former  consists  of  one  contact  per  unit  of  time, 
the  latter  of  two  per  unit.  A  given  carbon  atom  in 
the  benzene  ring  would  therefore  be  struck  twice 
by,  say,  its  right-hand  neighbor,  during  the  period 
in  which  its  left-hand  neighbor  bounded  against  it 
once.  Granted  the  plausibility  of  this  assumption, 
there  is  no  reason  why  these  vibrations  may  not  pass 
through  a  cycle  of  changes  such  that  contact  between 
two  atoms  occurs  alternately  once  and  twice  in  what- 
ever period  of  time  these  motions  require.2  The 
double  linking  in  this  case  would  be  alternately  on 
the  right  and  on  the  left  side  of  the  carbon  atom, 
and  as  the  oscillations  are  likely  to  be  extremely 
rapid,  to  all  practical  intents  and  purposes  position 
b  would  be  identical  with  position/: 


As  the  equivalence  of  the  six  hydrogen  atoms  is 
a  proved  fact,  independent  of  any  theory  about  the 

1  Ann.  Chem.  (Liebig),  162,  77  (1872). 

2  Mechanically,   this  is  rather  difficult  to  conceive  of.      Cf. 
Michaelis,  Ber.  d.  chem.  Gesell.  5,  463  (1872). 


THE  CONSTITUTION  OF  BENZENE 


43 


structure  of  the  ring,  this  hypothesis  of  the  "  oscil- 
lating double  linking  "  has  become  an  integral  part 
of  Kekule's  theory.  Without  it,  the  symmetry 
could  not  be  accounted  for.  However,  during  the 
years  that  elapsed  between  the  first  publication  of 
the  benzene  theory  and  its  emendation  as  just  given, 
several  other  formulae  were  proposed  to  fill  the  gap. 
Three  of  these  had  or  have  serious  claims  for  con- 
sideration; they  will  be  discussed  in  detail  below. 
Others,  such  as  the  one  given  by  Dewar  (1866) : 


are  lacking  in  symmetry,  and  therefore  are  not  to 
be  entertained  for  a  single  moment. 

The  three  formulae  which  have  equal  claims  with 
Kekule's,  when  considered  with  regard  to  the  sym- 
metry of  the  ring,  are  known  respectively  as  the 
prism,  the  diagonal,  and  the  centric  formulae.  They 
will  be  reviewed  in  the  order  named.- 

I.    The  Prism  Formula 

The  prism  formula  was  first  seriously  advocated 
by  Ladenburg  (1869).  This  formula  distributes 
the  six  extra  valences  as  follows : 


\7 


44          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 
This  diagram  is  the  plane  projection  of  a  prism  : 


It  may  be  seen  at  a  glance  that  the  prism  is  per- 
fectly symmetrical ;  there  can  be  only  one  form  of 
mono-substitution  product.  The  formula  also  ac- 
counts satisfactorily  for  the  observed  phenomena  of 
di-substituted  benzenes  :  three,  and  three  only,  can 
exist.  But  here  arises  a  peculiarity  of  the  prism 
formula ;  if  we  remember  how  Koerner  defined  the 
ortho,  meta,  and  para  positions  (p.  37),  and  if  we 
further  adhere  to  the  established  custom  of  number- 
ing the  ortho  position  1-2,  etc.,  then  the  carbon 
atoms  of  the  prism  must  not  be  numbered  in  regular 
order,  thus  : 


A 

but  as  follows : 


And  for  this  reason  :  the  para  position  is  that  which 
furnishes  but  one  tri-derivative.  This  condition  is 
satisfied  by  the  vertical  edges  of  the  prism ;  posi- 
tions 5,  3,  2,  and  6  all  are  symmetrical  with  respect 
to  1-4.  The  carbon  atoms  at  the  intersections  of 
the  sides  of  the  triangles  stand  in  meta  position 
toward  each  other ;  for  of  the  four  possible  com- 


THE  CONSTITUTION  OF  BENZENE  45 

binations  containing,  say,  the  atoms  1  and  3,  viz. 
1.3.5,  1.3.2,  1.3.4,  and  1.3.6,  only  the  last 
two  are  identical ;  the  meta  position  corresponds  to 
three  tri-derivatives.  The  ortho  atoms  lie  in  dif- 
ferent triangles,  for  position  1-2  yields  two  tri-de- 
rivatives. 

Ladenburg's  prism  formula  thus  leads  to  a  dif- 
ferent conception  of  the  relative  positions  of  the 
atoms  in  benzene ;  for  according  to  Kekule's  formula 
the  ortho  atoms  are  directly  united,  whereas  Laden- 
burg  places  them  apart.  Ladenburg's  para  atoms 
are  directly  coupled,  Kekule's  are  not ;  etc.  This 
separation  of  the  ortho  atoms  was  felt  by  Laden- 
burg  1  himself  as  an  objection  to  the  formula,  though 
he  continued  its  advocacy. 

The  prism  formula,  for  the  reason  that  it  com-  • 
pletely  explains  all  the  facts  observed  in  connec-  ? 
tion  with  isomerism,  is  thus  distinctly  superior  to 
Kekule's,  which  requires  the  additional  hypothesis  of 
an  oscillating  double  linking.  Yet  it  is  a  strange 
fact  that  at  no  time  did  the  prism  formula  supersede 
the  older  one.  None  of  the  investigators  mentioned 
in  the  earlier  part  of  this  chapter,  aside  from  Laden- 
burg  himself,  availed  themselves  of  it.  In  spite  of 
Ladenburg's  superior  logic  it  remained  almost  a 
scientific  curiosity.  This  was  partly  caused  by  the 
spatial  nature  of  the  prism  formula.  Stereo-chemi- 
cal considerations  were  regarded  with  extreme  dis- 
trust at  the  time  in  question,  and  chemists  carefully 
avoided  them.  The  chief  cause,  however,  lay  in  the 
unwieldy  formulae  to  which  the  prism  led  when  ap- 

1  Ann.  Chem.  (Liebig),  179,  174  (1875). 


46 


THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


plied  to  the  so-called  "  condensed  "  benzene  rings ; 
e.g.  naphthalene  : 

/K     /K 


Such  a  structure  is  certainly  not  simple. 

But  interesting  as  the  prism  formula  is,  and  ex- 
cellent though  the  arguments  in  its  favor,  it  can 
no  longer  figure  as  a  possibility.  In  1886,  A.  von 
Baeyer  began  a  series  of  experimental  investigations 
on  the  distribution  of  the  valences  in  benzene,  the 
first  result  of  which  was  to  show  the  untenability  of 
the  prism  formula.  Baeyer  studied  the  reduction 
products  of  benzene  derivatives,  with  the  idea  in 
mind  that  the  best  way  to  get  at  the  six  valences 
was  to  put  some  of  them  out  of  the  road.  Now  the 
prism  formula  and  the  Kekule  formula  lead  to  widely 
different  expectations  when  we  loosen  the  valences 
not  directly  occupied  in  holding  the  ring  together.  In 
Kekule's  formula  no  change  in  relative  positions  can 
take  place  when  we  pass  from  a  normal  to  a  hexa- 
hydrated  derivative ;  none  of  the  linkings  that  de- 
termine the  ortho  or  meta  or  para  position  are 
loosened : 


Not  so  with  the  prism ;  on  reducing  it  to  the  hexa- 
hydro  derivative,  only  one  of  the  three  para  positions 


THE  CONSTITUTION  OF  BENZENE 


47 


remains  intact.     This  is  readily  seen  from  the  fol- 
lowing formulae  : 


444 

Of  the  three  sets  of  para  positions,  viz.  1-4,  2-5, 
3-6,  but  one  remains  a  true  para  position  (1-4) ;  the 
other  two  have  assumed  ortho  relations.  If,  there- 
fore, a  benzene  compound  containing  two  or  three 
sets  of  para  substituents  still  contains  two  or  three 
para  sets  after  being  reduced,  the  prism  formula  can- 
not be  correct.  Baeyer's  experiments1  proved  this 
to  be  the  case.  Dioxyterephthalic  ester  has  the  fol- 
lowing structure  : 

C02C2H6 


C02C2H5 

because  it  readily  yields  hydroquinone.  On  reduc- 
tion with  sodium  amalgam  it  passes  into  succinylo- 
succinic  ester.  This  compound  results  from  the 
action  of  sodium  on  succinic  ester,  just  as  aceto- 
acetic  ester  is  formed  from  acetic  ester ;  and  its 
method  of  formation  leads  to  the  formula  : 

H  CO.OC2H6 

V 


A 
H  CO.OC2H6 

1  Ber.  d.  chem.  GeselL  19,  1797  (1888). 


48          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Now  in  succinylosuccinic  ester  the  hydroxyl  groups 
are  in  para  position  to  each  other,  likewise  the  carb- 
ethoxyl  groups.  The  same  is  true  of  dioxytere- 
phthalic  ester.  Two  sets  of  para  positions  have  thus 
remained  unaltered,  a  result  impossible  under  the 
prism  formula. 

The  behavior  of  phthalic  acid1  upon  reduction 
furnishes  a  similar  argument  against  the  prism. 
According  to  this  latter,  ortho  compounds  should 
be  converted  into  meta  : 


But  hexahydrophthalic    acid   behaves    exactly   like 
dimethylsuccinic  acid,  yielding  an  anhydride : 


CH8 

\^ 

'CO 


dH8 


>0 
<CH° 


Hexahydroisophthalic  acid,2  on  the  contrary,  which 
according  to  Ladenburg's  theory  should  be  an  ortho 
compound  : 


i  Ann.  Chem.  (Liebig),  258,  145  (1890). 

a  Baeyer  and  Villiger,  Ann.  Chem.  (Liebig),  276,  259  (1893). 


THE  CONSTITUTION  OF  BENZENE 


49 


does  not  give  an  anhydride.  The  reduction  of 
phthalic  and  isophthalic  acids  therefore  does  not 
alter  the  relative  positions  of  the  substituents.  After 
these  results,  the  prism  formula  has  not  a  leg  left  to 
stand  upon.1 

II.    The  Diagonal  Formula 

A.  Glaus,2  in  a  work  now  difficultly  accessible,  first 
suggested  that  the  constitution  of  benzene  might 
be  better  expressed  by  the  following  formula : 


As  originally  proposed,  this  structure  conflicted  with 
the  proved  existence  of  three  di-substitution  prod- 
ucts ;  for  each  carbon  atom  is  directly  connected 
with  three  others : 


Compounds  ab,  af,  and   ad   ought   therefore   to  be 
identical  —  in  contradiction  to  experience. 

To   remedy   this   defect   in  his   formula,    Glaus 8 
announced  that  the  "  para-bonds  "  were  not  like  ordi- 

1  Ladenburg  admits  the  weighty  evidence  against  his  formula, 
but  contends  that  some  benzene  derivatives  are  so  constructed. 
Ber.  d.  Chem.  Gesell.  20,  62  (1887). 

2  Theoretische  Betrachtungen  (Freiburg,  1867),  p.  207. 
»Cf.  Ber.  d.  chem.  Gesell.  Ij^WOJ  (1882);  20,  1423  (1887). 

B  R  A 

UNIVERSITY 


50          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

nary  ones  ;  first  of  all,  they  connected  atoms  that 
were  further  apart  than  is  ordinarily  the  case  ;  and 
secondly,  they  are  much  more  easily  ruptured.  The 
assumption  of  the  influence  oip  distance  on  affinity 
is  of  course  purely  hypothetical ;  the  length  of  line 
we  draw  on  paper  to  represent  the  connection  of 
atoms  can  have  no  possible  effect  upon  the  nature 
of  that  union.  But  the  assumption  that  these  para- 
bonds  were  somehow  different  from  ordinary  bonds, 
was  a  point  clearly  capable  of  experimental  investiga- 
tion. This  investigation  was  carried  out  by  Baeyer, 
in  the  series  already  referred  to.  As  Baeyer's  papers 
form  extremely  complicated  reading  matter,  on  ac- 
count of  the  fact  that  their  author  himself  changed 
his  point  of  view  several  times  during  the  course 
of  research,  I  can  do  no  better  than  to  give  literally 
a  portion  of  Baeyer's  address l  on  the  occasion  of  the 
Kekule  celebration,  in  which  he  sums  up  the  evidence. 
"  If  this  assumption  (as  to  the  difference  of  para- 
from  ordinary  bonds)  is  correct,  it  is  to  be  expected 
that  after  rupturing  one  bond  the  presence  of  the  other 
two  could  be  shown.  ^Experiment  proved,  however,  that 
only  double  Unkings  remained,  and  so  it  was  concluded 
that  benzene  contained  no  para-bonds.  To  this  Olaus 
objected  that  the  two  para-bonds  might  rearrange  them- 
selves to  form  double  Unkings : 


1  Serichte,  23,  1277  (1890). 


TEE  CONSTITUTION  OF  BENZENE 


51 


" At  the  first  glance  it  would  seem  easy  to  decide  this 
question  experimentally  by  reduction  of  terephthalic 
acid.  Provided  Claus  is  correct,  the  dihydro-acid  first 

formed  must  have  the  formula : 

H  X 
V 


H  X 

KekulS^s  formula  would  lead  to  an  acid  of  different 

constitution:  H  X 

X 


It  was  found  that  upon  extremely  careful  reduction 
there  resulted  the  compound  indicated  by  Clauses  view. 
But  at  the  same  time  observations  were  made  which 
showed  that  the  very  same  result  might  be  obtained  on 
the  basis  of  Kekule"*  s  formula. 
"  The  dihydro-acid : 


upon  reduction  furnishes  a  tetrahydro-acid  of  the  fol- 
lowing constitution :  H  X 


H 


HX 


52          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Here,  too,  the  reduction  has  proceeded  as  if  an  easily 
loosened  para-bond  were  present.  In  order  to  remove 
all  doubt  in  this  respect,  I  have,  together  with  Dr.  Rupe, 
reduced  muconic  acid,  and  have  arrived  at  the  very 
identical  result : 

<OOH  /COOK 

TT    f~\/ 
Hgv/c 
H  \CH 

I  >-  II 

^CH  .CH 

HC<  HQC^ 

\COOH  \COOH 

Muconic  acid  yields  a  hydromuconic  acid  of  corre- 
sponding type,  and  it  is  thus  shown  that  the  addition 
of  hydrogen  in  the  para  position  by  no  means  requires 
the  presence  of  a  para  linking  in  the  ring.  The  re- 
duction of  terephthalic  acid  may  thus  be  explained  by 
Kekule's  formula  : 

HK 


HX 

Baeyer  thus  arrives  at  the  conclusion  that  no  para- 
bonds  can  be  found  experimentally  in  the  benzene 
ring. 

III.    The   Centric  Formula 

Properly  speaking,  this  is  no  separate  formula, 
but  merely  a  modification  of  Claus's.  Pt  was  first 
proposed  by  Armstrong,1  almost  immediately  there- 
after by  Baeyer,2  and  finally  adopted  by  Glaus  in 

1  J.  Chem  Soc.  1887,  264,  682. 

2  Ann.  Chem.  (Liebig),  245,  118  (1888). 


THE  CONSTITUTION  OF  BENZENE  53 

this  modified  form.  It  supposes  that  the  extra  six 
valences  do  not  directly  unite,  but  are  attracted 
toward  the  centre  and  neutralize  each  other  all  of  a 
heap,  so  to  speak  : 


They  are  held  in  this  position  by  delicately  balanced 
forces,  so  that  if  anything  should  happen  to  one  of 
them,  the  rest  rearrange  themselves  according  to  the 
conditions  of  greatest  stability. 

There  is  no  rigid  proof  of  the  centric  formula. 
It  may  be  said  that  there  is  no  proof  at  all  of  it.  In 
its  nature  it  is  incapable  of  proof,  for  the  premise 
that  the  valences  are  held  in  position  by  forces  that 
admit  of  no  disturbance  except  by  complete  altera- 
tion, precludes  experimental  study.  The  formula 
is  merely  the  best  picture  we  have  of  the  complete 
symmetry  of  the  ring,  of  its  stability  toward  re- 
agents, and  of  its  difference  from  the  other,  better- 
known  forms  of  union  between  carbon  atoms.  By 
definition  it  avoids  these  difficulties.  Benzene  con- 
tains no  para-bonds  that  we  can  lay  hold  of;  if  it 
contains  double  linkings,  these  are  certainly  not  like 
the  ordinary  ones  of  the  fatty  series,  and  require  a 
special  hypothesis,  both  for  their  lack  of  additive 
powers  and  for  the  absence  of  isomeric  ortho  sub- 
stitution products.  Under  such  conditions  it  is 
much  better  to  use  an  entirely  characteristic  formula 
than  to  adhere  to  one  which  is  misleading  except 
under  interpretations  of  an  uncertain  nature. 


54          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Certain  facts  have  led  Baeyer  to  believe  that  there 
is  no  one  benzene  formula  —  that  both  the  centric 
and  the  Kekule  formulse  are  correct  ;  in  other  words, 
that  some  benzene  derivatives  possess  the  one,  some 
the  other  structure.  In  later  papers  than  the  one 
quoted,  he  advocates1  a  cross  between  the  original 
and  the  modified  Glaus  formula  for  phthalic  acid  ; 
theoretical  considerations  would  show  that  there  is 
perhaps  in  this  case  a  closer  connection  between  the 
para  atoms  than  is  given  by  the  centric  formula. 
On  the  other  hand,  phloroglucine  2  behaves  as  if 
it  really  contained  three  double  linkings.  With 
hydroxylamine  it  furnishes  an  oxime,  with  phenyl- 
hydrazine  a  hydrazide  ;  in  other  respects  it  is  un- 
doubtedly a  trioxybenzene.  The  following  formulse 
explain  the  reactions  mentioned  : 


CH2 


-NH .  NHC6H6 

JCH2  HCl^CH 

2=N .  NHC6H6  C  -NH .  NHC6H6 

It  would  therefore  seem  as  if  the  special  com- 
position of  a  benzene  derivative  exercised  a  decisive 
influence  upon  its  final  constitution :  a  result  in 
thorough  agreement  with  our  experiences  in  other 

i  Ann.  Chem.  (Liebig),  269,  172,  187  (1892). 

3  Ber.  d.  chem.  Gesell  19,  159  (1886);  24,  2687  (1891). 


THE  CONSTITUTION  OF  BENZENE  55 

fields  (cf.  Chap.  IV.).  The  "benzene  problem"  re- 
solves itself  into  a  series  of  special  problems,  from 
the  solution  of  which  we  may  expect  much  light 
to  be  shed  upon  the  problem  as  a  whole.  Baeyer's 
investigations  on  the  peculiar  nature  of  phthalic  acid 
have  not  be.en  extended  since  the  early  part  of  1892, 
which  is  greatly  to  be  regretted.  Many  examples  of 
the  phloroglucine  type  have  been  observed,  but  for 
the  present  they  have  added  nothing  to  the  benzene 
theory. 

A  fairly  complete  account  has  now  been  given  of 
the  work  carried  out  with  the  special  object  in  view 
of  determining  the  structure  of  benzene  and  its  de- 
rivatives. Many  other  investigations  have  shed 
sidelights  upon  the  question,  and  hardly  a  single  in- 
vestigator has  failed  to  seize  his  opportunity.  The 
most  prominent  of  these,  more  from  the  discussions 
they  have  raised  than  from  actual  gain  to  our  knowl- 
edge of  the  problem,  have  been  the  researches  upon 
the  so-called  physical  constants.  As  is  well  known, 
both  the  molecular  refraction  and  the  molecular  heat 
of  combustion  are  subject  to  "constitutive  influ- 
ences"; i.e.  the  values  of  these  constants  differ  for 
isomeric  substances,  the  difference  depending  upon 
differences  in  constitution.  Chief  among  the  con- 
stitutive details  which  must  be  taken  into  account 
is  the  nature  of  the  linking  between  the  carbon 
atoms,  each  double  and  each  triple  linking  exercis- 
ing a  marked  and  approximately  constant  influence. 
What  could  be  simpler,  then,  than  directly  to  observe 
the  refractive  and  thermochemical  constants  of  ben- 
zene, and  by  comparison  with  the  computed  values 
ascertain  the  constitution  of  this  devious  hydro- 


56          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

carbon  ?  Upon  this  as  a  basis,  Thomsen 1  and  Stoh- 
mann2  came  to  the  conclusion  that  the  heat  of  com- 
bustion of  benzene  is  incompatible  with  the  presence 
of  double  linkings,  whereas  Briihl 3  insisted  that  the 
refractive  constant  proves  the  existence  of  three 
double  bonds  in  the  very  same  substance.  This  ludi- 
crous contradiction  is  probably  a  mere  coincidence  ; 
in  fact,  by  taking  another  point  of  view,  Briihl 4  has 
endeavored  to  show  that  Stohmann's  figures  mean 
the  opposite  of  their  author's  conclusion.  Here  lies 
the  chief  difficulty  about  such  determinations  of  con- 
stitution ;  they  depend  largely  upon  one's  point  of 
view,  rather  than  upon  fixed  and  definite  standards. 
We  must  remember  that  constants  derived  from 
observations  in  the  fatty  series  cannot  safely  be  em- 
ployed to  prove  or  disprove  the  presence  of  group- 
ings in  the  aromatic  series.  If  benzene  contains 
"  double  linkings,"  these  must  certainly  be  different 
from  ordinary  fatty  double  bonds;  else  we  should 
not  be  put  to  such  trouble  to  find  them.  Whether 
or  not  we  employ  the  same  mechanical  device  to 
picture  these  two  widely  divergent  somethings  we 
call  double  bonds,  must  not  obscure  the  issue.  The 
refractometric  and  thermochemical  "  constants  "  have 
been  found  to  be  so  extremely  sensitive  to  slight  con- 
stitutional changes,  that  the  peculiarities  of  the  ben- 
zene structure  must  have  effects  far  beyond  our 
simple  guessing  powers  to  estimate. 

Other  attempts  have  been  made  to  ascertain  the 

1  Ber.  d.  chem.  Gesell.  13,  1808  (1880). 

2  J.  prakt.  Chem.  [2],  48,  453  (1893). 

8  Ann.  Chem.  (Liebig),  200,  139  (1880). 
*  Ber.  d.  chem.  Gesell.  27,  1065  (1894). 


THE  CONSTITUTION  OF  BENZENE  57 

secret  of  the  constitution  of  benzene  by  indirect 
means.1  They  depend  upon  more  or  less  uncertain 
analogies,  and  differ  as  widely  in  their  conclusions 
as  do  the  "  physical "  methods.  Their  main  interest 
lies  in  this  diversity  of  result  rather  than  in  their 
contribution  to  the  benzene  problem,  and  we  may 
therefore  omit  their  consideration  here. 

The  new  doctrines  recently  introduced  into  organic 
chemistry,  which  deal  with  the  spatial  arrangement 
of  the  atoms,  have  met  with  but  moderate  success  in 
their  application  to  the  benzene  ring.  Certain  forms 
of  isomerism,  it  is  true,  may  be  easily  explained  by 
their  aid.  Thus  Baeyer2  was  able  to  account  for 
the  existence  of  two  hexahydro-terephthalic  acids  as 
follows : 

H2        H2  H2        H2 

H    /^~^\    H  H      /--\.      COOH 

COOH  ><\ /<  COOH     COOH  ><\ /  <H 

H2     H2  H2      H2 

In  the  one  case,  the  carboxyl  groups  are  on  the  same 
side  of  the  plane  formed  by  the  benzene  ring,  in  the 
other  case  they  are  on  opposite  sides.  The  explana- 
tion is  a  transcription  of  that  employed  for  maleic 
and  fumaric  acids  (cf.  Chap.  VII.,  p.  163)-,  in  fact, 
Baeyer  recommends  the  terms  maleinoid  and  fuma- 
roid  for  describing  this  kind  of  isomerism.  As  to 
benzene  itself,  we  do  not  possess  any  definite  infor- 
mation concerning  the  arrangement  of  its  atoms  in 

1  A  long  list  of  these  is  given  in  Meyer-Jacobson,  Lehrbuch,  II, 
46  (1895).    Two  recent  examples  are:  V.  Meyer,  Ber.  d.  chem. 
Gesell.  28,  2776,  3195  (1895);  and  Hantzsch,  Ibid.  29,  958  (1896). 

2  Ann.  Chem.  (Liebig),  245,  137,  158  (1888). 


58  THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

space,  though  numerous  hypotheses  have  been  ad- 
vanced. Of  these,  but  two  call  for  mention  here  : 
that  of  Vaubel,1  because  its  author  is  making  a  syste- 
matic attempt  to  develop  it,  and  that  of  Sachse,2 
because,  while  geometrically  excellent,  it  is  incom- 
patible with  our  views  of  valence,  and  may  therefore 
lead  to  interesting  developments  of  our  valence  con- 
ceptions. Unfortunately,  the  peculiarities  of  both 
of  the  stereochemical  formulae  mentioned  cannot  be 
brought  out  without  the  aid  of  a  model,  so  that  no 
picture  of  them  can  be  given  here. 

In  conclusion,  it  may  be  worth  while  to  risk 
a  prophecy.  As  is  well  known,  certain  curious 
relationships  obtain  when  we  subject  benzene  deriva- 
tives to  chemical  action  ;  the  nature  of  the  substitu- 
ents  already  present  determines  the  position  the 
entering  substituent  must  take  up.  For  example, 
the  nitration  of  phenol  leads  to  a  mixture  of  the 
ortho-  and  para-nitro-phenols,  whereas  the  nitration 
of  benzoic  acid  leads  to  a  meta  derivative.  This 
curious  phenomenon  thus  far  lacks  an  adequate  ex- 
planation, though  several  attempts  have  been  made 
to  reduce  it  to  law.3  It  is  to  be  expected  that  the 
next  progress  in  the  elucidation  of  the  benzene  mys- 
tery will  come  from  this  field  of  investigation,  —  but 
what  the  results  will  be,  mortal  man  cannot  foresee. 

Kekule  lived  thirty  years  after  immortalizing  him- 
self and  his  "  theory  "  —  thirty  years  devoted  to  in- 
cessant labor  by  himself  and  thousands  of  others. 
But  in  spite  of  the  tremendous  activity  inspired  by 

1  Cf .  recent  and  current  numbers  of  J.  prakt.  Chem. 

2  Ztschr.  physik.  Chem.  10,  228  (1892). 

*  Cf.  Armstrong,  J.  Chem.  Soc.  1887,  682. 


THE  CONSTITUTION  OF  BENZENE  59 

the  benzene  theory,  in  spite  of  the  heroic  efforts  of 
men  like  Ladenburg  and  Baeyer,  the  final  answer  has 
yet  to  be  given  to  the  tantalizing  question  :  What  is 
the  constitution  of  C6H6  ?  When  will  it  come,  and 
whence  ? 


CHAPTER  IV 

THE  CONSTITUTION  OF  ACETOACETIC  ETHER 

THE  chapter  of  organic  chemistry  which  deals  with 
the  constitution  of  the  substance  called  acetoacetic 
ether,  prepared  by  Geuther  in  1863,  is  second  in  its 
importance  and  extent  only  to  that  on  benzene.  At 
this  day,  when  we  are  just  emerging  from  the  heated 
strife  of  diverging  opinion,  when  the  many  new  as- 
pects of  chemical  reaction  still  startle  us  with  their 
unexpectedness  and  variety,  it  is  impossible  fully  to 
appreciate  the  far-reaching  significance  of  the  revo- 
lution that  is  being  quietly  effected.  The  mass  of 
material  collected  is  appalling  in  its  vastness  and 
complexity  ;  but  fortunately,  during  the  past  year 
or  two,  much  insight  has  been  gained  into  the  nature 
of  the  puzzling  problem,  and  a  great  part  of  the 
amassed  facts  are  now  only  a  matter  of  detail. 

The  early  history  of  acetoacetic  ether,  though  quite 
complicated,  has  but  little  interest  to  us  now,  for 
the  complications  arose  from  insufficient  experimen- 
tation rather  than  from  difficulties  of  interpretation. 
A  full  treatment  of  this  portion  of  the  subject  has 
been  given  by  Johannes  Wislicenus,1  a  brief  extract 
from  which  will  suffice  here. 

Geuther's  first  paper  remained  practically  unknown, 
for  it  was  published  in  an  almost  inaccessible2  quarter; 

1  Ann.  Chem.  (Liebig),  186,  163-178  (1877). 

2  Gottinger  Anzeigen,  1863,  p.  281. 

60 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER       61 

it  contained  the  announcement  that  when  sodium  is 
dissolved  in  pure  ethyl  acetate,  the  chief  product  is 
a  sodium  compound  of  the  composition  C6H9NaO3. 
This  sodium  compound,  treated  with  acids,  gave  an 
ethereal  liquid  C6H10O3  ;  l  it  reacted  with  alkyl  iodi- 
des, replacing  sodium  by  alkyl.  Two  years  later, 
Frankland  and  Duppa  2  reported  a  series  of  products 
from  the  action  of  sodium  on  acetic  ether  after  sub- 
sequent treatment  with  ethyl  iodide.  These  prod- 
ucts were  ethylacetic  acid  ethyl  ester,  diethylacetic 
acid  ethyl  ester,  and  other  compounds,  which  proved 
to  be  identical  with  the  products  obtained  by  Geuther 
by  action  of  ethyl  iodide  upon  his  sodium  compound 
C6H9NaO3.  The  formation  of  these  latter  substances 
appeared  simple  enough,  since  Geuther  had  shown 
the  steps  of  the  reaction  ;  but  in  order  to  explain 
the  occurrence  of  the  first  two,  Frankland  and  Duppa 
assumed  that  sodium  forms  several  compounds  with 
ethyl  acetate,  notably  a  mono-  and  a  di-substitution 
product  : 

CH8COOC2H5  +  Na       =  CH2NaCOOC2H6  +  H 
and 

CH2NaCOOC2H6  +  Na  =  CHNa2COOC2H6  +  H 

which  then  reacted  quite  normally  with  ethyl  iodide  : 

CH2NaCOOC2H5  +  C2H6I     =  CH2(C2H6)COOC2H6  +  Nal 
+  2  C2H6I  =  CH(C2H6)2COOC2H6  +  2  Nal 


According  to  Frankland  and  Duppa,  then,  Geu- 
ther's  sodium  compound  was  only  a  part  of  the  reac- 
tion product.  As  to  its  constitution,  they  found  that 

1  Viz.  acetoacetic  ether.     •*** 

2  Ann.  Chem.  (Liebig),  137,  217  (1865);  138,  204,  32$  (1866). 


62          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

from  its  methyl  and  ethyl  substitution  products, 
methyl  and  ethyl  acetone  were  obtained  by  saponi- 
fication ;  and  they  accordingly  expressed  the  opinion 
that  the  compound  C6H9NaO3  was  really  sodium 
acetone-carboxylic  acid  ethyl  ester : 

CH8-CO-CHNa-CO-OC2H5 

Geuther1  did  not  accept  any  of  these  conclusions. 
He  regarded  the  oil  C6H10O3  as  an  acid  (he  called 
it  ethyldiacetic  acid);  he  was  unable  to  find  any 
trace  of  Frankland  and  Duppa's  supposed  sodium- 
substituted  acetic  ethers ;  and  finally  he  showed  that 
the  ethyl  derivative  of  the  sodium  compound,  which 
both  he  and  the  others  had  prepared,  gave  con- 
siderable quantities  of  butyric  ester  (ethylacetic 
<  ester)  on  simple  heating  with  sodium  e  thy  late. 
This  last  fact  completely  overthrew  Frankland  and 
Duppa's  hypothesis ;  for  sodium  ethylate  is  always 
formed  during  the  action  of  sodium  upon  acetic  ether. 

From  this  time  on,  until  the  classic  researches  of 
Wislicenus,  the  investigation  was  of  an  extremely 
desultory  nature,  consisting  for  the  most  part  of 
theoretical  disquisitions  of  a  reprehensible  character. 
Wislicenus  clearly  realized  the  necessity  of  working 
with  pure  materials,  and  of  making  sure  of  each  step 
before  passing  on.  His  work  extended  over  a  period 
of  several  years,  though  the  chief  publications  ap- 
peared in  1877.2 

In  order  to  properly  understand  Wislicenus's  stand- 
point, the  citation  of  his  reasons  for  accepting  the 
Frankland -Duppa  formula  for  acetoacetic  ether  is  de- 

i  Ztschr.  Chem.  1868,  58. 

*Ann.  Chem,  (Liebig),  186,  163  (1877);  190,  257  (1877). 


THE  CONSTITUTION   OF  AC  ETO  ACETIC  ETHER     68 

sirable.  The  passage  in  question,  moreover,  possesses 
considerable  historic  interest,  as  we  shall  see  later. 

"  If  acetoacetic  ether  is  really  ethyldiacetic  acid, 
it  is  difficult  to  reconcile  the  fact  that  upon  saponi- 
fication  by  alkalies  it  yields  carbonic  acid  and  acetone, 
with  the  circumstance  that  the  esters  of  this  acid 
(made  by  action  of  alkyl  iodides  upon  the  sodium 
salt)  do  not  also  give  acetone  when  saponified,  but 
the  corresponding  alkylsubstituted  acetones.  Thus, 
Fraiikland  and  Duppa  obtained  from  methyl  aceto- 
acetic ether,  which,  according  to  Geuther,  can  only  be 
the  methyl  ester  of  ethyldiacetic  acid,  a  methylated 
acetone  (methyl-ethyl-ketone),  from  ethylacetoacetic 
ether,  ethyl  acetone  (methyl-propyl-ketone),  etc. 

"The  alkyl  groups  which  take  the  place  of  the 
sodium  atom  in  sodium  acetoacetic  ether  (sodium 
ethyldiacetate  according  to  Geuther)  are  found  in 
the  products  of  saponification  attached  directly  to 
carbon;  and  in  all  probability  the  products  first 
formed  likewise  contain  them  attached  to  carbon. 
But  if  this  is  the  case,  then  the  sodium  atom  of 
sodium  acetoacetic  ether  (whose  place  of  course  is 
taken  by  the  alkyl)  is  not  attached  as  in  salts;  i.e. 
to  oxygen,  but  directly  to  the  carbon  of  the  nucleus, 
The  following  empiric  equations  absolutely  require 
analogous  constitutions  for  acetoacetic  ether  and  its 
alkyl  substitution  products  : 

1.  C6H10Os  +.2  NaOH         =  Na2C03  +  C2H6OH  +  CH3COCH8 

2.  C6H9(K)03  +  2NaOH    =  Na2C03  +  C2H5OH+CH3COCH2(R) 

3.  C6H8(R)203  +  2NaOH  =  Na2CO3  +  C2H6OH  +  CH8COCH(R)2 


This  analogy  would  be  wanting  if   C6H10O3  were 
ethyldiacetic  acid,  C6H9(R)O3  its  alkyl  ester.     Nor 


64          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

is  it  apparent  in  what  relation  the  di-alkyl  aceto- 
acetic  ethers  stand  to  these  others  if  we  accept 
Geuther's  view.  Perhaps  this  innate  difficulty 
explains  why  Geuther  scarcely  mentions  the  di-alkyl 
acetoacetic  ethers  in  his  various  papers,  and  avoids 
their  discussion  altogether. 

"  As  against  Frankland's  conception  of  C6H9NaO3 
as  sodium-acetone-carboxylic-acid  ethyl  ester, 

CH3-CO-CHNa-CO-OC2H6 

we  might  have  set  objections  to  the  assumed  direct 
substitution  of  hydrogen  attached  to  carbon  by 
metals.  However,  since  we  have  become  acquainted 
with  similar  processes  in  other  organic  substances 
(as  e.g.  acetylene,  nitroethane),  such  an  assumption 
loses  its  startling  peculiarity.  At  this  day  it  no 
longer  surprises  us  that  a  carbon  atom  which  is 
directly  united  to  two  CO-groups  can  hold  metals 
in  place  of  hydrogen.  For  the  union  with  one  nitro 
group  suffices  to  produce  a  similar  condition  of 
4  electrochemical  polarization '  in  the  nitro-paraf- 
fines  —  the  simple  loss  of  hydrogen  in  the  acetylenes 
achieves  the  same  end." 

The  theoretical  views  just  quoted,  then,  were  Wis- 
licenus's  guide  during  his  investigations.  His  experi- 
mental results  are  well  known,  and  require  but  a 
short  review.  First  of  all,  he  found  that  acetoacetic 
ether  under  no  circumstances  reacted  with  more  than 
one  atom  of  sodium  —  it  contains  but  one  directly 
replaceable  hydrogen  atom,  contrary  to  the  views  of 
Frankland  and  Duppa.  Upon  replacing  the  sodium 
by  an  alkyl  radical,  Wislicenus  found  that  the  result- 
ing alkyl-acetoacetic  ether  was  again  able  to  take 


UNIVERSITY 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     65 

up  an  atom  of  sodium  —  it  is  therefore  possible  to 
indirectly  replace  two  hydrogen  atoms  in  acetoacetic 
ether  by  metals.  Similar  results  were  obtained  from 
the  action  of  sodium  ethylate  in  place  of  sodium. 
If  the  sodium  compounds  are  heated,  decomposition 
takes  place;  sodium  acetoacetic  ether  yields  chiefly 
ethyl  acetate  ;  sodium  ethyl  acetoacetic  ether  yields 
ethyl  butyrate  ;  di-ethyl  acetoacetic  ether,  which 
does  not  react  with  sodium  ethylate  in  the  cold, 
gives  considerable  quantities  of  di-ethyl  acetic  ether. 
These  results  completely  cleared  up  the  nature  of 
Frankland  and  Duppa's  reaction,  as  is  readily  seen. 
Wislicenus  was  thus  able  to  show  that  the  "  aceto- 
acetic ether  syntheses  "  are  best  carried  out  with  pure 
materials,  as  presence  of  excess  of  sodium  ethylate 
invariably  complicates  matters.  The  value  of  these 
syntheses  was  greatly  enhanced  by  Wislicenus's  study 
of  the  peculiar  behavior  of  acetoacetic  ether  and  its 
substitution  products  toward  saponifying  agents. 
Thus,  dilute  alkalies  (aqueous  potash  or  barium 
hydroxide)  split  these  compounds  largely  as  follows  : 

CH3CO-C(X)  (Y)  1COOC2H6  +  2  H20   =  C2H5OH  +  H2C08 

+  CH3CO-CH(X)(Y) 

into  alcohol,  carbonic  acid,  and  ketones  (ketonic 
hydrolysis).  Concentrated  (preferably  alcoholic) 
alkalies,  on  the  other  hand,  break  up  the  molecule 
at  another  point, 


CH3COC(X)(Y)-COOC2H5  +  2H2O   =    C2H6OH+CH3COOII 
i  +  CH(X)(Y)COOH 

into  alcohol,  acetic  acid,  and  a  substituted  acetic  acid 
(the  so-called  acid  hydrolysis).  By  means  of  aceto- 
acetic ether  as  a  stepping-stone,  then,  we  may  pre- 


66          THE  SPIRIT  OF  OEGANIC  CHEMISTRY 

pare  any  desired  ketone  (containing  one  methyl 
group)  and  any  desired  acid  of  the  acetic  acid  series 
by  the  proper  choice  of  alkyl  halides. 

But  these  syntheses  by  no  means  limit  the  applica- 
bility of  acetoacetic  ether  ;  for  this  substance  is  like 
the  hat  from  which  the  magician  takes  out  a  trunk- 
ful  of  oddities.  If  we  act  upon  sodium  acetoacetic 
ether  with  ethyl  chloracetate,  we  can  get  aceto-sue- 
cinic  ether,  and  by  hydrolysis  succinic  acid  : 


CH8COCH  |  Na  ;  COOC2H5+CH2  |  Cl  j  COOC2H6  =  NaCl-f 

'"-'          CH3CO-CHCOOC2H5 
I 
CH2COOC2H6 


•CH8CO;CHCOO    c2H6  +  3H2O  =  2  C2H5OH  +  CH3COOH 

+  CH,COOH 


CH2COOH 

and  by  suitable  combinations,  a  huge  variety  of 
di-  and  poly-basic  acids.  Another  type  of  synthesis 
occurs  when  we  act  upon  the  sodium  compounds 
with  iodine  ;  acetoacetic  ether  for  instance,  gives 
diacetosuccinic  ether  : 

CHgCOCH  i  Na'j  COOC2H5  CH8CO-CHCOOC2H5 

+I2  =  2NaI  +  | 

CHsCOCH  ]  Na  |  COOC2H5  CH8CO-CHCOOC2H5 

from  which  another  endless  series  of  compounds  arises. 
Furthermore  many  acetoacetic  ether  derivatives, 
being  ketones,  may  be  reduced  to  the  corresponding 
hydroxy-compounds  : 

CH8COCH2COOC2H5  +  H2  =  CH8CHOH-CH2COOC2H5 

Thus,  acetoacetic  ether  yields  /3-hydroxybutyric  ether. 
This  on  heating  loses  water,  and  gives  crotonic  ether  : 

CH8CHOH-CH2COOC2H6  =  H2O  +  CH8CH=CHCOOC2H5 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER      67 

which  enables  us  to  pass  to  the  unsaturated  series 
of  acids.  In  short,  acetoacetic  ether  is  our  most 
valuable  synthetic l  reagent. 

It  would  almost  seem  from  these  results  of  Wisli- 
cenus  that  the  history  of  acetoacetic  ether  might 
have  stopped  then  and  there  ;  but  thousands  of 
pages  of  controversy  testify  to  the  contrary.  The 
most  immediate  and  most  important  difference  of 
opinion  centred  around  the  query :  Are  not  the 
properties  of  acetoacetic  ether  better  expressed  by 
the  isomeric  formula  of  an  oxy-crotonic  ether  : 
CH3-C-  (OH)  =  CH-C02C2H5  ? 

The  difference  between  the  two  formulae  is  very 
slight ;  one  readily  passes  into  the  other  by  the  sim- 
ple shifting  of  a  hydrogen  atom.  We  may  ask, 
then,  what  the  arguments  are  in  favor  of  the  "  oxy  " 
formula.  The  question  is  complicated  by  many 
others,  however,  and  though  their  solution  was 
worked  out  simultaneously  for  the  most  part,  a 
separate  treatment  of  each  is  imperative.  These 
questions  are  as  follows  : 

1.  Why  is   acetoacetic   ether  possessed   of    acid 
properties  ?     Wislicenus  speaks  of  "  electrochemical 
polarization,"  of  the  influence  of  two  carbonyl  groups 
on  the  methylene  between  them  : 

/CO-CHs 
CH2< 

\CO-OC2H6 

Is  this  a  general  law  ?  Does  any  real  significance 
attach  to  the  reference  to  electrical  phenomena  ? 

2.  Wislicenus   asserts   that  when   alkyls   replace 
sodium,  they  do  so  literally  ;  they  take  the  place  of 

1  E.g.  note  Behrend's  synthesis  of  uric  acid  (p.  106). 


68          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

the  sodium.  Such  a  view  has  been  almost  axiomatic 
in  chemistry  ;  but  is  it  really  and  invariably  true  ? 
And  if  doubt  be  possible  in  this  case,  why  must 
acetoacetic  ether  and  its  sodium  compound  necessa- 
rily have  the  same  constitution  ? 

3.  To  what  extent  do  the  various  condensation 
products  of  acetoacetic  ether  and  its  analogues  cor- 
respond to  one  or  the  other  formula  ?     Ketones  con- 
dense differently  from  hydroxyl  compounds,  so  that 
the  possibility  of  a  distinction  seems  evident. 

4.  The  simple  shifting  of   a  hydrogen  atom  re- 
moves the  difference  between  the  "  ketone  "  and  the 
"  oxy  "  formulae.     May  we  not  assume  such  a  shifting 
to  take  place  during  reactions,  the  direction  of  the 
oscillation  to  be  determined  by  the  reagents  employed? 
Would  not  the  two  formulae  then  become  identical? 
Do  we  really  know  of  any  case  where  isomerism  of 
the  subtle  nature  demanded  here  actually  exists  ? 

Verily,  a  startling  array  of  problems,  well  calcu- 
lated to  arouse  differences  of  opinion.  Their  diffi- 
culty has  resulted  in  one  feature  common  to  every 
solution  proposed.  The  very  fact  that  so  many 
questions  are  asked  about  acetoacetic  ether  shows 
that  they  cannot  easily  be  answered  by  a  study  of  the 
compound  itself.  Therefore,  each  author  has  searched 
for  analogies  throughout  the  whole  domain  of  organic 
chemistry.  It  is  this  feature  that  complicates  the 
issue,  and  which  has  made  it  of  such  vital  importance 
to  the  whole  subject.  It  is  this  feature,  moreover, 
which  has  caused  most  of  the  confusion  and  violence 
of  the  struggle ;  for  reasoning  by  analogy  is  a  dan- 
gerous proceeding  —  all  the  more  so  when  the  mother- 
substance  is  Protean  in  its  character. 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     69 

I.  THE  ACTION  OF  SODIUM  ON  SIMILAR  COMPOUNDS 

To  test  the  theory  of  "electrochemical  polariza- 
tion," Wislicenus  searched  for  other  compounds  con- 
taining a  methylene  group  adjacent  to  two  carbonyls. 
Under  his  immediate  inspiration,  Conrad1  found  such 
a  substance  in  the  well-known  malonic  ether  : 


xCO 
CH;/ 

XX)-OC2H5 

which  contains  the  desired  grouping,  and  is  sec- 
ond in  importance  only  to  acetoacetic  ether  itself. 
Malonic  ether  forms  a  sodium  substitution  product 
in  much  the  same  way  as  acetoacetic  ether.  A  slight 
difference  exists  inasmuch  as  sodium  malonic  ether 
is  decomposed  by  water,  and  sodium  acetoacetic 
ether  is  not  ;  and  further,  that  malonic  ether  can 
directly  replace  both  its  methylene  hydrogen  atoms 
by  sodium,  whereas  acetoacetic  ether  cannot.  Ma- 
lonic ether  is  an  important  factor  in  the  syntheses  of 
fatty  acids,  since  all  the  substituted  malonic  acids 
show  a  typical  reaction  of  malonic  acid  itself  ;  viz.,  of 
splitting  off  carbon  dioxide  on  heating,  with  forma- 
tion of  a  member  of  the  acetic  acid  series  : 

<OOH  /H 

=  CH2<  +C02 

OOH  \COOH 

Similar  reactions  toward  sodium  are  shown  by  all 
substances  possessing  the  group  postulated  by  Wis- 

licenus : 

I 
—  CO  -CH- 


.  Chem.  (Liebig),  204,  121  (1880). 


70          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Such  are,  for  instance,  acetylacetone  : 
CH3CO-CH2-CO-CH3 
acetone  dicarboxylic  ether  : 

,CH2-CO-OC2H6 

\CH2-CO-OC2H5 
benzoylacetone  : 

C6H5CO-CH2-CO-CH8 
benzoylacetic  ether: 

C6H6CO  -  CH2  -  CO  -  OC2H6 

besides  many  others  which  will  be  referred  to  later. 
A  general  law  thus  seems  to  hold  here. 

Yet  Wislicenus  stated  only  half  of  the  truth  ;  for 
in  1890  Freer  l  found  that  acetone  itself, 

CH8-CO-CHS 

which  certainly  does  not  contain  a  methylene  group 
situated  between  two  carbonyls,  is  capable  of  form- 
ing a  sodium  derivative,  whose  reactions  are  similar 
in  nearly  every  respect  to  those  of  sodium  acetoace- 
tic  ether.  This  reaction  of  Freer's  is  a  general  one  ; 
it  is  shown  by  other  ketones,2  as  well  as  by  acetic 

aldehyde  :  8 

CHs-CO-H 

The  simple  presence  of  a  carbonyl  group,  then, 
suffices  for  the  formation  of  sodium  compounds,  pro- 
vided, of  course,  that  a  neighboring  hydrogen 
be  available. 


*Amer.  Chem.  J.  13,  308  (1860);  15,  582  (1893);  17,  1  (1895). 
*Ibid.  19,  878  (1897). 
«  Ibid.  18,  552  (1896). 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER      71 

Wislicenus's  theory  of  "polarization"  thus  resolves 
itself  into  a  general  property  of  ketones  (and  prob- 
ably aldehydes);  there  is  no  connection  with  elec- 
trical phenomena  as  far  as  we  know.  On  the  other 
hand,  it  must  be  said  that  certain  other  so-called 
"negative"  groups  besides  carbonyl  possess  the 
power  of  enabling  neighboring  hydrogen  atoms  to 
react  with  sodium.  Thus,  Victor  Meyer l  found 
that  benzyl  cyanide  : 

C6H5-CH2-CN 

gives  a  sodium  compound  which  reacts  with  ethyl 
iodide,  attaching  the  ethyl  to  the  methylene  group. 
Likewise,  cyanacetic  ether  :  2 

/CN 
CH2< 

\CO-OC2H5 
and  malo-nitrile  :  3 

/CN 
CH2< 
\CN 

form  similar  sodium  compounds.  We  thus  have  to 
deal  with  an  undoubted  influence  of  neighboring 
groups  upon  each  other;  but  what  the  explanation 
may  be,  is  at  present  unknown. 

II.    WHERE  IS  THE  SODIUM  IN  SODIUM-ACETOACETIC 
ETHER  ? 

The  fact  that  such  a  question  could  ever  have 
arisen  marks  one  of  the  most  important  steps  taken 
by  chemistry.  Frankland  and  Wislicenus  found  no 

1  Ber.  d.  chem.  Gesell.  20,  534,  2944  (1887). 

2  Henry,  Compt.  rend.  104,  1618  (1887);  Haller,  ibid.  1626. 

8  Schmidtmann,  Ber.  d.  chem.  Gesell.  29,  1171  (1896);  Hesse, 
Amer.  Chem.  J,  18,  723  (1896). 


72          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

difficulty  in  answering  it  :  the  sodium,  "  whose  place 
is  of  course  taken  by  the  alkyl,"  is  attached  to  car- 
bon, since  the  alkyl  groups  are  eventually  found 
there.  If  the  sodium  were  attached  to  oxygen,  why 
then  the  alkyl  groups  would  be  found  there.  Upon 
such  reasoning  as  this  the  whole  superstructure  of 
synthetic  chemistry  rests. 

It  is  true,  the  validity  of  this  argument  had  occa- 
sionally been  questioned.  Thus,  it  is  well  known 
that  potassium  cyanide  gives  normal  cyanides  with 

alkyl  iodides  : 

R-C  =  N 

whereas  silver  cyanide  gives  isocyanides  : 


Similar  phenomena  occur  with  nitrites  and  sulfites. 
Yet  this  difficulty  was  avoided  by  the  assumption  of 
different1  constitutions  of  the  potassium  and  silver 
salts  in  question,  or  by  a  so-called  rearrangement 
of  the  product  after  its  formation. 

In  1887,  however,  Michael2  found  that  sodium 
acetoacetic  ether,  which,  when  treated  with  ethyl 
iodide,  gave  a  C-derivative,3  gave  a  derivative  of  the 
oxy-formula  with  chlorcarbonic  ether  :  4 

CHs-C-CO-COaCaHg) 
II 
CH-CO-OC2H6 

1  Cf.  H.  Goldschmidt,  Ber.  d.  chem.  Gesell.  23,  253,  2180  (1890). 

2  And  simultaneously  Claisen  (cf.  Her.  d.  chem.  Gesell.  22,  1763). 
8  Claisen  (Ann.  Chem.   (Liebig),  277,  162)  has  proposed  that 

when  the  entering  radical  becomes  attached  to  carbon,  it  be  called 
a  C-derivative,  if  to  oxygen,  an  O-derivative.  This  plan  has  been 
universally  adopted. 

*  J.  prakt.  Chem.  [2],  37,  473  (iStf  ).     |  ^  <l  \ 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     73 

The  literal  interpretation  of  the  formation  of  this 
carbethoxy -acetoacetic  ether  would  lead  to  the  oxy- 
formula  for  sodium  acetoacetic  ether ;  the  equally 
literal  explanation  of  the  older  syntheses  of  Frank- 
land  and  Wislicenus  would  attach  the  sodium  to 
carbon.  If  sodium  acetoacetic  ether  is  a  single 
definite  compound,  as  there  is  every  reason  to  be- 
lieve,1 then  one  or  the  other  of  these  syntheses  is 
abnormal,  and  requires  a  special  hypothesis. 

One  result  stands  out  clearly  from  this  experi- 
ment; viz.,  that  we  cannot  deduce  the  constitution  of 
a  substance  from  that  of  any  of  its  derivatives,  whose 
method  of  formation  includes  a  metallic  substitution 
product.  The  most  notable  confirmation  of  this 
theorem  is  given  by  the  history  of  the  oximes  (see 
Chap.  VIII.).  The  question  of  the  constitution  of 
acetoacetic  ether,  therefore,  is  entirely  independent 
of  the  structure  of  sodium  acetoacetic  ether,  and  all 
the  arguments  used  to  defend  either  the  oxy  or 
ketone  formula  of  the  free  compound,  which  involve 
reactions  of  the  sodium  salt,  are  now  ruled  out  of 
court.  This  independence  cannot  be  shown  more 
convincingly  than  by  the  fact  that  Claisen  and 
Michael,  two  strong  adherents  of  the  ketone  formula 
for  the  free  ether,  are  also  champions  of  the  oxy 
structure  of  the  sodium  compound. 

Two  questions  now  arise  :  If  acetoacetic  ether  and 
its  sodium  compound  have  different  structures,  how 
is  one  formed  from  the  other  ?  And  if  sodium  aceto- 
acetic ether  can  give  both  C-  and  O -derivatives, 
which  of  the  two  are  we  to  consider  abnormal  ? 

1  Cf.  Elion,  Recueil  trav.  chim.  3,  240  (1884), 


74          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

As  to  the  first  query,  but  little  is  known.  How- 
ever, it  is  largely  a  matter  of  indifference.  The 
important  question  is,  What  is  the  constitution  of 
the  free  compound  and  of  its  sodium  salt  ?  Our 
preconceived  notions  as  to  how  a  reaction  ought  to 
take  place  must  wait  until  we  know  how  it  does 
take  place.  All  such  doctrines  as  affinity  of  sodium 
for  oxygen,  polarization,  mutual  attraction,  and  the 
like,  valuable  though  they  are  to  the  individual  as 
a  spur  to  action  and  a  guide  to  research,  must  not 
dominate  the  subject  as  a  whole,  to  the  exclusion  of 
the  real,  and  perhaps  most  simple,  cause.  In  this 
connection  it  may  be  well  to  refer  to  the  only  theory 
of  the  formation  of  acetoacetic  ether  which  rests 
upon  an  experimental  basis,  for  it  leads  to  the  oxy- 
structure  of  the  sodium  salt.  Claisen  and  Lowman  J 
found  that  ethyl  benzoate  adds  sodium  ethylate  : 


OC2H6 

C2H6 
NaOC2H5  = 


/ 

C6H6C=0 

This  sodium  addition  product,  brought  into  contact 
with  ethyl  acetate,  reacts  as  follows  :  2 


!OC2H5    Hj 

C2Hs    H  |^C-C02C2H5  =  C6H5C(ONa)=CHC02C2H5 
ONa"~~H  +  2  C2H6OH 

giving  alcohol  and  sodium  lenzoylacetic  ether.     The 
transfer  of  this  fact  to  the  action  of  sodium  upon 

1  Ser.  d.  chem.  GeselL  20,  651  (1887);  21,  1154  (1888). 

2  Such  condensations,  produced  by  sodium  ethylate,  are  ex- 
tremely frequent  and  very  important.     Nearly  all  ketonic  acids 
and  poly-ketones  are  made  by  this  means.     The  process  has  been 
extended  chiefly  by  Claisen,  W.  Wislicenus,  and  Michael. 


THE  CONSTITUTION   OF  ACETOACETIC  ETHER      75 

acetic  ether  is  simple.  Pure  acetic  ether  is  not 
attacked  by  sodium  ;  the  presence  of  a  trace  of 
alcohol  is  necessary  ;  this  forms  sodium  ethylate, 
which  adds  to  a  molecule  of  acetic  ether  ;  the  addi- 
tion-product then  reacts  with  a  second  molecule  to 
form  sodium  acetoacetic  ether  and  alcohol  ;  the  alco- 
hol produced  reacts  with  more  sodium,  and  thus  the 
process  goes  on  :  l 

/OC2H6  /OC2H6 

/  + 


CH3C  +  NaOC2H6  = 

^0  \ONa 


!  OC2H5      H  ; 

I  OC2H6  -f  H  i\CCO-OC2H6  =  2C2H6OH 


N'~ONa~        H  ''  +  CH8C(ONa)=CHCO-OC2H5 

The  second  question,  which  of  the  two  forms  of 
derivatives  is  abnormal,  is  more  difficult  to  answer. 
So  far  but  one  solution  has  been  proposed,  which  is 
far  from  being  rigidly  proved.  Yet  the  ideas  it  con- 
tains have  been  so  fruitful  in  directing  research,  and 
promise  to  so  thoroughly  modify  our  conceptions  of 
the  nature  of  chemical  reactions,  a*s  to  warrant  a 
somewhat  detailed  consideration.  This  solution  is 
the  addition  theory  of  Michael.2 

The  idea  that  many  reactions  proceed  by  addition 
and  subsequent  splitting  off  is  not  new.  It  was 
advanced  by  Baeyer3  many  years  ago,  and  has  been 
verified  in  many  cases  ;  we  need  only  refer  to  the 
polymerization  of  aldehyde  to  aldol,  with  subsequent 

1  Claisen  has  given  a  summary  of  this  theory,  Ann.    Chem. 
(Liebig),  297,  92  (1897). 

2  J.  prakt.  Chem.  [2],  37,  486  (1^.       /  $ 
8  Ber.  d.  chem.  Gesell.  3,  63  (1870). 


76          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

loss  of  water  to  form  crotonaldehyde,  and  to  Perkin's 
reaction  (see  Chap.  II.).  The  formation  of  esters 
from  salts,  on  the  other  hand,  had  always  been 
regarded  as  a  process  of  direct  interchange  of  the 
most  pronounced  type.  Michael  assumes  as  a  start- 
ing-point that  compounds  containing  metal  and 
oxygen  contain  that  metal  attached  to  oxygen. 
(This  assumption  is  not  an  integral  part  of  the 
theory,1,  but  the  work  of  recent  years  seems  to  bring 
out  this  fact  prominently.)  Given  a  compound 
X-Y  reacting  with  sodium  acetoacetic  ether,  action 
may  occur  by  replacement  or  by  addition.2  If  by 
replacement,  then  the  result  is  an  O-derivative.  If 
by  addition,  then  addition  occurs  in  such  a  manner 
that  the  group  for  which  sodium  has  the  greatest 
attraction  (say  Y)  attaches  itself  to  the  carbon  atom 

connected  to  NaO : 

Y 

CHs-C-ONa 

I 
C2H6C02-CH 

X 

When,  subsequently,  NaY  is  split  off,  X  remains 

attached  to  carbon  : 

CHSC=O 

I 
C2H5CO2CHX 

1  Nor  is  it  universally  accepted.     It  is  still  impossible  to  state 
definitely  whether  the  sodium   in  the  derivatives  mentioned  is 
attached  to  oxygen.    The  important  fact  to  remember  is  that  710 
matter  where  the  sodium  is  situated,  its  position  has  nothing  to  do 
with  the  constitution  of  the  free  compounds. 

2  Or  in  both  manners  simultaneously.     Cf.  Claisen,  Ann.  Chem. 
(Liebig),  277,  162  (1893);  Wheeler  and  Boltwood,  Amer.  Chem. 

£*  J.  18,  381  (1896). 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER       77 

Whether  addition  or  substitution  is  to  take  place 
depends  upon  circumstances  at  present  unknown, 
but  clearly  capable  of  empirical  determination. 
When  addition  occurs,  the  general  course  of  reaction 
is  as  given  above,  since  halogen  is  almost  invariably 
one  of  the  constituents  of  the  reacting  substance. 

Michael  has  extended  these  considerations  to  all 
other  cases  where  two  forms  of  derivatives  exist  of  a 
single  mother-substance.  Thus,  potassium  cyanide 
and  silver  cyanide  may  easily  have  the  same  struc- 
ture ;  one  may  react  with  ethyl  iodide  by  addition, 
the  other  by  substitution.  Michael  himself  has  a 
44  positive-negative  "  theory,  from  which  he  deduces 
the  phenomena  by  the  relative  attraction  of  various 
groups  for  each  other.  But  this  theory,  like  so 
many  others  which  are  purely  deductive,  has  failed 
in  several  cases  1  because  of  the  insufficiency  of  its 
foundation  ;  and  for  the  present  it  has  no  place  in 
chemical  history. 

The  addition  theory,  it  is  safe  to  predict,  will  play 
a  very  important  part  in  the  future  development  of 
chemistry.  Yet  a  word  of  caution  may  not  be  amiss. 
If  sodium  acetoacetic  ether  reacts  with  ethyl  iodide 
by  addition,  then  the  very  similarly  constituted  sodium 
salts  of  the  oxymethylene  compounds  (p.  83),  e.g. 

=CH-ONa 


ought,  as  far  as  we  can  see,  to  act  in  the  same 
manner  ;  yet  sodium  oxymethylene  camphor  gives  an 
O-derivative  2  with  ethyl  iodide.  We  see,  therefore, 

1  Cf.  Marburg,  Ann.  Chem.  (Liebig),  294,  89  (1896). 

2  Claisen,  Ann.  Chem.  (Liebig),  281,  317  (1894). 


78          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

that  the  theory  still  requires  careful  control  by 
actual  experiment.  Then,  too,  the  formation  of 
diacetosuccinic  ether  from  sodium  acetoacetic  ether 
(p.  G6)  is  difficult  to  reconcile  with  the  oxy-formula 
and  the  idea  of  addition. 

But  the  chief  obstacle  to  the  growth  of  the  addi- 
tion theory  lies  deeper  than  these  detailed  exceptions. 
If  we  are  going  to  explain  reactions  by  means  of 
addition  products  which  we  do  not  or  cannot  isolate, 
our  explanation  loses  its  defmiteness.  It  becomes 
simply  a  possible  explanation,  and  its  conclusions 
are  by  no  means  binding.  The  recent  history  of 
Michael's  hypothesis  but  serves  to  emphasize  the 
necessity  of  critical  caution.  We  owe  most  of  our 
experimental  knowledge  of  addition  reactions  to 
Nef,  who  has  very  lately  based  a  far-reaching  and 
fundamentally  new  conception  of  organic  chemistry 
upon  his  results.1  It  is  not  time,  nor  is  this  the 
place,  to  attempt  a  criticism  of  this  extension  of  the 
addition  theory.  But  in  the  preliminary  work  lead- 
ing up  to  his  present  standpoint,  Nef  has  assumed 
as  many  as  six2  distinct  intermediate  products  in 
certain  reactions,  not  one  of  which  supposititious 
stepping-stones  has  been  isolated.  It  is  clear  that 
more  definite  ideas  of  reactions  are  necessary  if  we 
are  to  gain  real  insight  into  their  mechanism.  On 
the  other  hand,  it  must  be  admitted  that  transition 
periods  are  characterized  by  exaggeration,  and  we 
should  not  be  hasty  in  our  judgment  of  a  valuable 
working  hypothesis. 

-"•  J  Ann.  Chem.  (Liebig),  298,  202  (1897). 

2  Ibid.  280,  290  (1894);  287,  347  (1895).  Cf.  V.  Meyer,  Ber.  d. 
chem.  Gesell.  27,  3156  (1894). 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER      79 

III.     THE  CONDENSATION  PRODUCTS  OF  ACETOACETIC 
ETHER 

At  a  first  glance  it  would  seem  as  if  the  nature  of 
these  substances  would  immediately  clear  the  matter 
up;  for  we  have  to  decide  between  a  ketone  and  a 
hydroxy  compound,  whose  reactions  are  usually 
widely  different.  Upon  second  glance,  however,  it 
is  apparent  that  the  ordinary  reagents  for  carbonyl 
will  not  help  us,  for  on  the  basis  of  either  formula  we 
can  arrive  at  identical  products.  Thus,  acetoacetic 
ether  adds  hydrocyanic  acid  as  well  as  sodium  bisul- 
fite ;  but  both  of  the  addition  products  may  be  readily 
assumed  to  form  from  an  oxy-crotonic  ether  ;  e.g. 


CH3v 

\C-OH  \C-CN 

||  +  HCN  =  | 

/•-ITT  OTT 

xV^-Ll  X^/JC12 

C2H50(X)  C2H5OCO 

In  fact,  it  is  due  to  the  frequent  formation  of 
derivatives  of  the  oxy-formula  upon  condensation 
that  the  controversy  has  continued  so  long.  It  is 
needless  to  give  a  list  of  examples  here ;  the  discus- 
sion of  a  single  case  will  suffice.  Knorr 1  found  that 
acetoacetic  ether  forms  a  hydrazone  with  phenyl- 
hydrazine,  which,  however,  easily  loses  water  and 
passes  into  phenyl  methyl  pyrazolone : 2 


.______2\  CH8C=N 

H2C-CO  +  N-C6H6  =  >N-C6H8 


.  +  H20  +  C2H5OH 

1  Ann.  Chem.  (Liebig),  238,  147  (1886). 

2  This  is  the  usual  formula  of  this  compound  ;   two  isomeric 
structures,  however,  are   equally  possible.     Knorr,  Ann.  Chem. 
(Liebig),  279,  186  (1893). 


80          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Nef1  subjected  the  phenylhydrazone  to  a  closer 
examination  ;  he  found  that  it  can  be  oxidized  to 
a  compound  containing  two  hydrogen  atoms  less, 
which  is  apparently  an  azo-body,2  and  concluded  that 
acetoacetic  ether  phenylhydrazone  is  really  phenyl- 
hydrazino-crotonic  ether  : 

CH3C-NH-NH-C6H6 

C2H6OCOCH 

This  formula  is  of  course  derived  from  the  oxy-struc- 
ture  of  acetoacetic  ether,  and  is  used  by  Nef  as  an  argu- 
ment for  it.  However,  Nef  subsequently3  showed 
in  another  connection  that  when  phenylhydrazine 
reacts  with  carbonyl  groups,  it  does  so  first  by 
addition  :  , 

CH8CO  +  H2N-NHC6H6  /?_!  H 

=  CH8C^!NH-NH-C6H6 
CH2CO-OC2H6  |     '  -------- 

CH2CO-OC2H6 

This  addition  product,  by  loss  of  water,  can  readily 
pass  into  either  the  hydrazone  or  the  hydrazide  : 

,x 
^N-NH-C6H6+H20 


HN  NH  P  H 
CH8C/  C2H6OCOCH2 

8|\OH 
C2H6OCOCH2 


\ 

\ 
\ 


C2H6OCOCH 

Thus  no  matter  what  the  constitution  of  this  con- 
densation product,  it  does  not  help  us  to  find  the 
formula  of  the  mother-substance.  Similar  consider- 
ations apply  to  nearly  all  other  condensations,  so 
that  they  are  of  no  avail. 

*Ann.  Chem.  (Liebig),  266,  70  (1891). 

*     2  See  Freer,  Amer.  Chem.  J.  21,  23  (1899),  for  the  real  struc- 
ture of  this  "  azo-compound." 

8  Ann.  Chem.  (Liebig),  270,  289,  333  (1892). 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     81 

With  one  important  exception,  however.  The  con- 
densation of  acetoacetic  ether  with  ortho-formic  ether1 
can  hardly  be  explained  by  any  other  than  the  ketone 
formula.  The  substances  react  to  produce  diethoxy- 
butyric  ether : 

:;—;c2H60' 
CH8C  !  o  I     |  CaHsO  ;\CH 

I    X)C2H6       HC02C2H6 

L    + 


v/ii3\^  i  (_)  i       i  v^2nsv-f  i_>QIJ   __    CJJ  Q^ 

"+ ""cT^o""/  i  NDC 

C2H6OCOCH2  C2H5OCOCH2 


It  is  difficult  to  see  how  such  a  product  could  be 
formed  from  an  oxy-crotonic  ether,  except  on  the 
assumption  of  a  variety  of  intangible  addition  reac- 
tions. If  any  one  single  reaction  can  be  relied  upon 
to  settle  the  controversy,  we  have  here  a  proof  of  the 
ketone  formula  of  acetoacetic  ether. 


IV.  MUST  WE  ASSUME  A  SHIFTING  HYDROGEN  ATOM 
IN  ACETOACETIC  ETHER  ? 

We  have  just  seen  that  all  derivatives  formed 
from  acetoacetic  ether  by  addition  or  by  means  of 
its  metallic  compounds  cannot  help  us  decide  upon 
its  constitution,  the  only  exception  being  the  for-— N 
mation  of  diethoxy-butyric  ether.     To  sum  up  our  J 
results  in  a  general  way,  we  should  be  inclined  to 
call  acetoacetic  ether  a  ketone,  chiefly  from  lack  of 
valid  reasons  for  considering  it  an  oxy-compound. 
Attempts  have  not  been  wanting  to  ascertain  the 
presence  of  a  hydroxyl  in  the  substance  ;    but  the 
interpretation    of    the    observed    facts    has    varied  I 
with  the  standpoint  of  the  observer.     The  following 


i  Claisen,  Ber.  d.  chuj^G**!ll~S&,  1005  (1896). 
* A 

}f  T*i 

UNIVERSITY 


82          THE  SPIE1T  OF  OEGANIC  CHEMISTRY 

account  must  be  largely  a  presentation  of  the  per- 
sonal opinions  of  the  various  investigators. 

Geuther,1  who  was  the  first  one  to  propose  the 
oxy-crotonic  formula,  tried  the  action  of  acetyl  chlo- 
ride upon  acetoacetic  ether,  as  well  as  upon  succiny- 
losuccinic  ether  (p.  47).  The  latter  readily  forms 
a  di-acetate  ;  the  former  did  not  react  until  high 
temperatures  were  reached  ;  hydrochloric  acid  was 
split  off,  but  no  acetate  was  formed.  Yet  in  spite 
of  this  marked  difference,  Geuther  2  did  not  hesitate 
to  declare  the  two  substances  to  be  similar  in  struc- 
ture, viz.  to  contain  hydroxyl  groups.  Considerably 
later,  Nef3  examined  the  action  of  acetic  anhydride 
upon  acetoacetic  ether  ;  he  found  that  after  pro- 
longed boiling,  about  two  per  cent  of  the  theoretical 
yield  of  O-acetyl  acetoacetic  ether  was  really 
obtained.  Nef,  too,  interpreted  this  result  to  mean 
the  presence  of  hydroxyl  in  the  substance  ;  many 
others,  however,  drew  the  opposite  conclusion. 
Indeed,  it  hardly  seems  reasonable  that  a  genuine 
hydroxy  compound  should  give  so  small  a  quantity 
of  ester  after  such  energetic  treatment. 

The  forced  conclusions  of  Geuther  and  Nef  are 
rendered  still  more  improbable  by  the  investigation 
of  a  series  of  substances  containing  the  group  postu- 
lated in  oxy-crotonic  ether,  viz., 

-C-OH 

II 
-CH 

1  Cf.  Wedel,  Ann.  Chem.  (Liebig),  219,  87  (1883). 

2  I.e.,  p.  119.    Cf.  Ann.  Chem.  (Liebig),  244,  190  (1887). 

3  Ann.  Chem.  (Liebig),  276,  212  (1893).   Cf.  v.  Pechmann,  ibid. 
278,  226  (1893). 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     83 

Such  substances  are  the  so-called  "formyl"  or  "oxy- 
methylene  "  compounds  of  Claisen  and  W.  Wis- 
licenus,  usually  prepared  by  the  sodium  ethylate 
condensation  of  esters  and  ketones  with  formic  ether  ; 
e.g.  formyl-  or  oxymethylene-propionic  ether  : 


._/?_CA?«: 

HC  !  H  ;  +  CHO  =  HC  -  CHO  +  C2H5OH 

C02C2H6  C02C2H5 

These  formyl  compounds  (which  closely  resemble 
the  acetyl  compounds  in  their  synthetic  preparation 
and  their  general  constitution)  really  have  the  iso- 
meric  structure  of  oxymethylene  derivatives  :  1 

CH3 

C=CH-OH 

CO-OC2H6 

They  react  with  benzoyl  chloride,  with  acetic  anhy- 
dride, with  phosphorus  ^'chloride,  to  form  the  cor- 
responding derivatives  with  excellent  yields  ;  these 
are  all  undoubted  hydroxyl  reactions,  and  are  given 
only  slightly,2  if  at  all,  by  acetoacetic  ether.  The 
conclusion  thus  seems  justified  that  acetoacetic  ether 
does  not  contain  hydroxyl. 

Here  is  where  the  matter  rests  to-day,  as  far  as 
acetoacetic  ether  itself  is  concerned;  an  unbiassed 
summary  of  all  the  details  given  certainly  points  to 
the  ketone  formula  for  the  free  substance,  and  ren- 
ders the  oxy-formula  of  its  sodium  salt  probable. 
To  a  certain  extent,  both  formulse  are  thus  justified 
and  reconciled. 

i  Ann.  Chem.  (Liebig),  281,  306  (1894). 
«  Cf.  Nef,  ibid.  276,  238  (1893). 


84         THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

However,  the  participants  in  this  history  builded 
better  than  they  knew  ;  for  the  most  important  result 
of  the  whole  agitation  has  arisen  from  the  inves- 
tigation of  a  proposed  explanation  which  at  the 
start  had  little  in  its  favor.  The  hypothesis  referred 
to  is  the  well-known  theory  of  pseudomerism,  intro- 
duced by  Baeyer,1  developed  by  Laar,2  Jacobson,3 
Hantzsch  and  Herrmann,4  and  others,  and  enriched 
by  a  variety  of  names,  such  as  tautomerism,  desmo- 
tropy,  merotropy,5  etc.  This  theory  owes  its  origin 
to  the  fact  that  certain  substances  seem  to  possess 
more  than  one  structure  ;  i.e.  they  either  give  de- 
rivatives of  two  or  more  mother-substances,  of  which 
only  one  really  exists  ;  or  their  synthesis  makes  sev- 
eral formulae  equally  probable  for  them.  Examples 
of  the  first  case  are  isatinef  which  gives  derivatives 
of  the  so-called  "  lactime  "  and  "  lactame  "  types  : 

/  N   *v  /NH\ 

c'H<co)C"°H  C6H<co>C° 

Isatine  Pseudo-isatine 

Lactime  Lactame 

and  phloroglucine?  which  usually  behaves  like  trioxy 
benzene,  yet  gives  a  tri-oxime  derived  from  the  tau- 
tomeric  tri-keto-hexamethylene  :  8 

OH  CO  C  =  NOH 

CH2/\CH2 


HON  =  Cx^c  =  NOH 
CH2  CH2 

1  Ber.  d.  chem.  Gesell.  16,  2189  (1883).     2  Ibid.  18,  648  (1885). 
8  Ibid.  20,  1732  (1887).  *  Ibid.  20,  2801  (1887). 

5  Michael,  J.  prakt.  Chem.  [2],  46,  208  (1892). 

6  Baeyer,  Ber.  d.  chem.  Gesell.  15,  2093  (1882). 

*  Baeyer,  ibid.  19,  159  (1887).  »  Cf.  p.  54. 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     85 

Examples  of  the  second  case  are  nitrosophenol,  which 
can  be  prepared  by  the  action  of  nitrous  acid  upon 
phenol,1  as  well  as  by  action  of  hydroxylamine  upon 


OH 


quinone  : 2 


v 

NO  O  NOH 

and  phenyl  tolyl  formamidine,3  which,  whether  pre- 
pared from  formanilide  and  toluidine,  or  from  f ormo- 
toluide  and  aniline  : 

/NBC§Hi| 

1 


/ 

HC<;o" 


!  O  H2  |  NC7H7  =  HC^ +  H2O 

NHC7H7 


,NHC7H7 
H2  !  NC«H6  =  HC<  +  HaO 

>NC6H6 


turns  out  to  be  one  and  the  same  substance. 

This  general  phenomenon  is  now  known  indiffer- 
ently by  all  the  terms  mentioned  abovev  the  most  com- 
mon designation  being  that  of  tautomerism.  Much 
confusion  of  ideas  has  resulted  hereby,  so  that  the 
need4  of  a  systematic  designation  has  become  press- 
ing ;  but  unfortunately,  no  uniform  terminology  has 
as  yet  been  adopted.  The  name  tautomerism  was 
originally  connected  with  a  particular  theory,  viz. 

1  Baeyer  and  Caro,  ibid.  7,  967  (1874). 

2  H.  Goldschmidt,  ibid.  17,  213  (1884). 

«Cf.  Wheeler,  Amer.  Chem.  J.  19,  367  (1897);  20,  853  (1898)  ; 
see  also  the  diazo-amido  compounds,  p.  204. 

*  Cf.  Claisen,  Ann.  Chem.  (Liebig),  291,  46  (1896). 


86          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Laar's l  hypothesis.  Laar  assumed  that  the  various 
formula  of  the  substances  mentioned  above  are  but 
apparently  different ;  they  differ  merely  in  the  posi- 
tion of  a  single  hydrogen  atom,  and  become  identi- 
cal if  we  suppose  the  hydrogen  atom  in  question  to 
be  continually  oscillating  between  its  two  positions.2 
Laar's  hypothesis,  in  this  form,  has  not  met  with 
much  favor ;  the  more  general  view  is  that  such  sub- 
stances have  only  one  structure,  but  that  during 
certain  reactions  they  assume  the  other  (pseudo-) 
forms.3 

Now  acetoacetic  ether  and  oxy-crotonic  ether  may 
be  regarded  as  a  pair  of  tautomeric  or  pseudomeric 
substances.  We  should  merely  have  to  decide  which 
of  the  two  formulse  appeared  most  frequently  in  re- 
actions, and  assign  that  formula  to  the  free  com- 
pound; the  other  would  then  be  tautomeric.  This, 
indeed,  was  the  commonly  accepted  explanation  of 
the  behavior  of  acetoacetic  ether  not  so  very  long 
ago.  We  have  seen  that  the  establishment  of  a 
separate  individuality  for  sodium  acetoacetic  ether 
has  done  away  with  much  of  the  necessity  for  any 
such  hypothesis. 

It  must  be  admitted  that  the  theory  of  pseudomer- 
ism  does  not  satisfy  one,  for  it  is  too  intangible,  too 
indefinite,  too  much  of  a  glittering  generality.  It 
is  practically  an  evasion  of  the  issue.  This  seems 
to  have  been  felt  strongly  by  Nef,  who  has  been  a 
strenuous  opponent  of  the  idea.  His  vigorous  cham- 

1  Per.  d.  chem.  Gesell.  18,  618  (1885);  19,  730  (1886). 

2  Cf.  Knorr,  Ann.  Chem.  (Liebig),  279,  186  (1894). 

3  Knorr,  I.e.  293,  97  (1896),  has  given  a  closer  definition  of 
tautomerism.     See  also  I.e.  303,  133  (1898),  footnote. 


THE  CONSTITUTION   OF  ACETOACETIC  ETHER      87 

pionship  of  the  oxy  formula  was  probably  due  to  a 
desire  to  explain  all  the  reactions  of  acetoacetic  ether 
without  recourse  to  such  a  vague  hypothesis.  It 
cannot  be  said,  however,  at  least  not  at  present,  that 
the  addition  theory  is  less  vague l  than  tautomerism. 
Indeed,  it  would  seem  as  if  most  of  Nef's  conten- 
tions in  this  field  were  erroneous.  He  assumed  that 
all2  1-3  diketones  are  substances  directly  compara- 
ble ;  but  we  have  seen  that  formyl  compounds  differ 
markedly  from  acetoacetic  ether  in  their  behavior, 
and  thus  cannot  have  a  similar  structure.  As  to 
tautomerism,  Nef  declared  that  the  whole  idea  rested 
upon  insufficient  experimentation  3  ;  that  no  example 
of  the  subtle  isomerism  required  by  tautomerism  is 
known. 

But  while  the  words  were  being  penned,  investi- 
gations of  these  very  phenomena  were  going  on  in 
four  different  laboratories,  with  sufficiently  startling 
results.  The  publications  of  Claisen  and  Wilhelm 
Wislicenus  will  stand  as  classics  in  the  domain  of 
pseudomerism,  as  models  of  experimentation  in  one 
of  the  most  difficult  fields  of  the  science*.  Wislicenus  * 
has  found  that  formyl  phenyl  acetic  ether  exists  in 
two  modifications  ;  the  a-compound  (a  liquid)  seems 
to  have  the  formula  : 

C6H5 
CH(OH)=C-COOC2H6; 

%    i  Cf.  Ber.  d.  chem.  Gesell.  25,  1760  (1892);  also  J.prakt.  Chem. 
[2],  46,  189  (1892). 

2  Ann,  Chem.  (Liebig),  270,  332  (1892);  276,  240  (1893);  277, 
60,  74  (1893). 

3  Ibid.  266,  137  (1891);  276,  240  (1893);  287,  353  (1895). 
*  Ann.  Chem.  (Liebig),  291,  147  (1896). 


88          THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

it  is  a  weak  acid,  and  colors  ferric  chloride  solution. 
The  /3-modification  (solid)  has  the  structure  : 

C6H5 
CHO-HC-COOC2H6; 

it  is  a  much  stronger  acid  than  the  a-compound,  and 
does  not  color  ferric  chloride.  These  two  substances 
can  be  readily  converted  into  each  other  by  simple 
heating  or  by  use  of  solvents.  High  temperatures 
favor  the  a-form  ;  solutions  of  either  substance  in 
chloroform  soon  contain  chiefly  a-,  in  alcohol,  the  &-. 
Claisen1  has  found,  among  other  compounds,2  that 
dibenzoyl  acetyl  methane  and  tribenzoyl  methane 
each  exist  in  similar  modifications  ;  the  a-,  or  hy- 
droxy,  form  : 


(OH)  -  CH8  ^C(OH)  -  C6H6 

-  C6H6  C^CO  -  C6H6 

\CO-C6H5  \CO-C6H6 

and  the  £-,  or  ketone,  form  : 

/CO-CH3  /CO-C6H6 

H-C^CO-C6H6  H-CC  CO-C6H6 

\CO-C8H5  \CO-C6H6 

In  respect  to  behavior  toward  ferric  chloride,  Claisen's 
substances  resemble  Wislicenus's;  the  a-  or  enolz  forms 
give  a  color  reaction,  the  0-  (keto  or  aldo)  forms  do 
not.  Similarly,  the  a-modifications  of  all  these  sub- 
stances are  more  stable  at  high  temperatures.  Yet 

1  Ann.  Chem.  (Liebig),  291,  25  (1896). 

2  For  a  similar  case,  see  Guthzeit,  Ann.  Chem.  (Liebig),  285, 
35  (1895).     Also  Knorr,  ibid.  293,  70  (1896),  where  a  number  of 
cases  are  experimentally  treated. 

8  The  term  enol  is  used  as  a  class  name  for  this  kind  of  hydroxy- 
compound,  keto  and  aldo  for  the  corresponding  isomeres. 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     89 

a  most  curious  difference  exists  between  the  Claisen 
and  the  Wislicenus  bodies  ;  for  whereas  Claisen's 
keto  substances  are  neutral,  and  his  enols  strong 
acids,  both  of  Wislicenus's  are  acids,  the  aldo  being 
much  stronger  than  the  enol.  How  this  contradic- 
tion of  ideas  will  resolve  itself,  it  is  difficult  to 
foretell ;  as  matters  stand  to-day,  the  experimental 
evidence  confirms  both  views.  , 

It  has  thus  been  experimentally  demonstrated  that 
substances  exist  which  are  capable  of  possessing  both 
the  enol  and  the  keto  structures  : 

-  C(OH)=C  -  CO  - 

and 

_  CO  -  CH  -  co  - 
I 

Which  of  the  two  structures  is  the  most  stable,  de- 
pends upon  the  nature  of  the  appended  radicals,  upon 
the  temperature,  and  upon  the  character  of  the  sol- 
vent used.  It  is  now  merely  a  question  of  time  until 
we  shall  be  familiar  with  all  the  conditions  necessary 
to  determine  one  or  the  other  constitution.  Laar's 
hypothesis  hereby  loses  any  remnants  of  probability 
it  possessed  —  under  given  conditions  we  always  have 
a  definite  substance  before  us.  At  the  same  time, 
the  theory  of  pseudo-forms  receives  an  experimental 
basis  ;  for  at  certain  temperatures,  or  in  certain  solu- 
tions, when  the  enol  is  changing  to  keto,  or  vice  versa, 
both  substances  are  present ;  and  if  simple  solution  in 
an  "  indifferent "  medium,  such  as  alcohol  or  chloro- 
form, is  capable  of  effecting  the  transformation,  com- 
pounds which  can  react  with  the  substance  must 
possess  that  ability  to  a  still  more  marked  degree. 


90          THE  SPIBIT  OF  ORGANIC  CHEMISTRY 

We  can  readily  see  how  the  future  of  organic  chem- 
istry must  wait  upon  the  development  of  the  theory 
which  ascribes  to  the  reagent  the  power  of  determin- 
ing the  constitution  of  the  substance  it  attacks.  It  is 
not  an  extravagant  comparison  to  place  this  new 
doctrine  upon  the  same  plane  as  Kekule's  benzene 
theory. 

In  conclusion,  a  reference  to  the  "  physical  con- 
stants "  of  the  substances  which  have  been  discussed 
may  not  be  amiss.  The  physical  constants  have 
always  been  drawn  into  such  extended  controversies 
upon  constitution.  The  general  objection  may  be 
made  to  them  that  they  represent  an  extrapolation, 
and  that  deductions  from  them  are  not  legitimate 
when  applied  to  substances  whose  chemical  behavior 
is  so  uncertain  (cf.  p.  56).  During  the  present 
controversy,  however,  the  reliability  of  such  physi- 
cal determinations  of  constitution  has  been  greatly 
strengthened  ;  for  Briihl's l  results  from  the  value  of 
the  index  of  refraction,  W.  H.  Perkin,  Sr.'s2  observa- 
tions of  magnetic  rotation,  and,  finally,  J.  Traube's 3 
new  theory  of  molecular  volumes,  have  severally  and 
collectively  agreed  with  the  conclusions  of  purely 
chemical  investigations.4  Eventually,  no  doubt,  when 
such  close  agreement  between  theory  and  observation 
will  have  become  the  rule,  the  problem  of  ascertaining 

1  Ber.  d.  chem.  Q-esell.  25,  366  (1892)  ;  J.  prakt.  Chem.  [2],  50, 
196  (1894)  ;  Ann.  Chem.  (Liebig),  291,  137,  217  (1896). 

2  J.  Chem.  Soc.  61,  836  (1892)  ;  Ann.  Chem.  (Liebig),  291,  185 
(1896). 

3  Cf.  Ann.  Chem.  (Liebig),  290,  43  (1895)  ;  ibid.  291,  188  (1896)  ; 
Ber.  d.  chem.  Gesell.  29,  1715  (1896). 

*  This  applies  also  to  the  absorption  of  electric  waves.  Cf .  Drude, 
Ber.  d.  chem.  Gesell.  30,  957  (1897). 


THE  CONSTITUTION  OF  ACETOACETIC  ETHER     91 

the  structures  of  complicated  substances  will  resolve 
itself  into  a  glance  into  the  spectrometer,  controlled, 
it  may  be,  by  a  specific  gravity  determination.  Such 
an  outcome  is  greatly  to  be  desired  ;  but  for  the  pres- 
ent the  organic  chemist  must  patiently  bide  by  his 
furnaces  and  retorts,  toiling  in  the  sweat  of  his  brow 
to  wrest  Nature's  secrets  from  her. 


CHAPTER  V 

THE  URIC  ACID  GROUP 

THE  products  of  animal  and  vegetable  metabolism 
have  always  exercised  a  peculiar  fascination  upon 
the  chemical  investigator.  In  the  first  place,  these 
substances  were  the  sole  subject-matter  of  organic 
chemistry  until  1828,  when  Wohler  proved  the  feasi- 
bility of  organic  synthesis.  Secondly,  many  of  these 
substances  are  of  economic  and  medicinal  importance, 
and  the  knowledge  of  their  structure  held  out  hopes 
of  commercial  gain.  And  finally,  the  processes 
whereby  Nature  evolves  these  complicated  deriva- 
tives from  the  simple  materials  at  her  command  are 
brought  nearer  their  comprehension  by  a  knowledge 
of  the  detailed  organization  of  their  molecules. 

This  last  incentive  has  been  peculiarly  stimulating 
in  the  case  of  uric  acid.  This  substance,  a  constant 
product  of  normal  human  physiology,  assumes  far 
greater  significance  in  human  pathology.  Its  exces- 
sive secretion  is  responsible  for  a  large  number  of 
ailments,  of  which  we  need  only  mention  rheumatism 
and  stone  in  the  bladder.  It  is  no  wonder,  then,  that 
uric  acid  has  attracted  considerable  attention  in  the 
medical  world,  and  that  this  interest  has  reacted  upon 
the  chemist.  Incidentally,  a  number  of  compounds 
closely  related  to  uric  acid  have  been  investigated 
because  of  their  use  as  stimulants  and  drugs. 

92 


THE  URIC  ACID  GROUP  93 

The  first  elaborate  investigation  of  uric  acid  was 
published  by  Wohler  and  Liebig1  in  1838.  This 
treatise  is  a  classic  in  its  experimental  comprehensive- 
ness. It  brings  a  wealth  of  new  material  to  light ; 
but,  owing  to  the  state  of  chemical  theory  at  the 
time,  this  material  hardly  serves  us  now  in  determin- 
ing the  structure  of  the  acid.  We  shall  therefore 
pass  it  by,  for  lack  of  space;  but  the  reader  who 
wishes  fully  to  appreciate  the  greatness  of  these 
pioneers  should  not  fail  to  peruse  this  masterpiece  of 
their  united  genius. 

The  continuation  of  this  investigation  was  taken 
up  by  Schlieper,2  who  added  a  number  of  new  com- 
pounds to  the  already  long  list,  and  above  all  by 
Baeyer,3  to  whom  we  owe  the  first  systematic  relation- 
ship among  the  numerous  derivatives.  It  is  impossi- 
ble to  recount  here  the  intricate  experimental  details, 
or  even  the  marvellous  chemical  instinct,  with  which 
Baeyer  unravelled  his  maze  of  facts.  We  must  be 
satisfied  with  a  synopsis  of  his  main  results. 

Baeyer  shows  that  uric  acid  and  its  host  of  deriva- 
tives may  in  their  turn  be  regarded  "as  derived  from 
a  compound  N2C4O3H4,  which  he  calls  barbituric  acid. 
Barbituric  acid  was  found  to  break  down  into  am- 
monia, carbon  dioxide,  and  malonic  acid  when  saponi- 
fied ; 4  Baeyer  therefore  looked  upon  it  as  malonyl 
urea: 

,CO  -  NH 
CH2  \CO 

\CO-BfH 

1  Ann,  Chem.  (Liebig),  26,  241  (1838). 

2  Ibid.  55,  251  ;  56,  1  (1845).  «  Ibid.  137,  1,  199  (1863). 
*  Ibid.  130,  143  (1864). 


94      r    THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Barbituric  acid  yields  a  mono-  and  a  di-brom  sub- 
stitution product,  in  which  the  bromine  replaces 
hydrogen  in  the  methylene  group.  If  these  bromine 
atoms  are  exchanged  for  hydroxyls,  there  are  obtained 

dialuric  acid : 

,CO  -  NH 

CH(OH)    \CO 
\3H-NH 


(which  may  also  be  called  hydroxybarbituric  acid, 
or  tartronyl  urea),  and  dihydroxybarbituric  acid  : 


CO  -  NH  ,CO  -  NH 

NCO,   or 
\CO  - 


. 

d 


(OH)2         CO,   or  CO  cO  +  H2O 


NcO 
-  NH 


commonly  known  as  alloxan  (or  mesoxalyl  urea). 

When  dialuric  acid  is  heated,  a  substance  called 
hydurilic  acid  is  formed  (for  an  explanation  of  this, 
see  below).  Hydurilic  acid,  in  its  turn,  when  treated 
with  nitric  acid,  breaks  down  into  alloxan  and  either 
violuric  or  dilituric  acids.  Violuric  acid,  according 
to  Baeyer,  is  nitroso-barbituric  acid;  it  is  now  re- 
garded as  isonitroso-barbituric  acid : 1 

,CO  -  NH 
(~>= 


CNOH   Sco 

\3O  -NH 


Dilituric  acid  is  nitrobarbituric  acid  : 

.CO  -  NH 

HC 


(N02) 
\CO 


)     NcO 
-NH 


1  It  may  also  be  looked  upon  as  the  oxime  of  alloxan.    Ceresole, 
Ber.  d.  chem.  Gesell.  16,  1133  (1883). 


THE   URIC  ACID   GROUP  95 

The  reasons  for  these  formulae  are  simple  enough : 
reduction  of  both  violuric  and  dilituric  acids  leads  to 
an  amido  compound  called  uramil;1  and  uramil, 
when  treated  with  nitrous  acid,  passes  into  dialuric 
acid.  Dialuric  acid  being  %^ro^barbituric  acid, 
uramil  must  be  amicfobarbituric  acid  : 

,CO-NH 

H(5-NH2     \3O 

\3O-NH 

and  the  formulae  of  violuric  and  dilituric  acids  result 
as  a  combination  of  these  facts  with  the  empirical 
composition  of  the  substances. 

When  uramil  is  treated  with  cyanic  acid,  the 
cyanate  first  formed  rearranges  itself  as  does  am- 
monium cyanate,  and  a  urea-derivative  called  pseudo- 
uric  acid  is  the  result.  It  receives  this  name  because 
it  has  the  empirical  composition  of  uric  acid,  viz. 
C5N4H4O3  +  H2O ;  its  constitution  is  : 

NH-CO 

CO/  CH-NH-CO-NH2 

NH-CO 

Baeyer  believed  that  if  pseudo-uric  acid  could  be 
made  to  lose^orue  molecule  of  water,  the  resulting 
cyananiide  2  derivative  would  be  uric  acid,  to  which 

1  This  had  previously  been  prepared  by  Liebig  and  Wohler,  by 
the  action  of  sulphur  dioxide  upon  alloxan  (thionuric  acid  is 
formed  as  an  intermediate  product). 

2  Urea,  NH2  — CO— NH2,  passes  by  (indirect)  loss  of  water  into 
cyananiide,  N  =  C  -NH2,  which  in  its  turn  takes  up  water  (directly) 
to  form  urea. 


96 


THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


he  thus  ascribed  the  following  constitution  : 

NH-CO 
C0<  CH-NH-CO==N 


NH-CO 


It  may  be  said  in  passing  that  Baeyer's  efforts  to  effect 
this  synthesis  of  uric  acid  were  in  vain,  and  that 
his  formula  was  not  generally  adopted ;  all  the  other 
structures  developed  by  him  stand  until  this  day. 

To  facilitate  reference  to  these  compounds,  with 
which  the  subsequent  pages  will  deal  frequently,  the 
following  table  given  by  Baeyer  will  be  found  very 
convenient : 


N2C403H4 

Malonyl  urea 

Barbituric  acid 

N2C408H3-OH 

Monohydroxy  do.  do. 

Dialuric  acid 

N2C403H2-(OH)2 

Dihydroxy  do.  do. 

Alloxan 

N2C4O3H2=NOH 

(Iso-)nitroso  do.  do. 

Violuric  acid 

N2C4O3H3-NO2 

Nitro  do.  do. 

Dilituric  acid 

N2C4O3H3-NH2 

Amido  do.  do. 

Uramil 

N2C4O3H3-NH2  (CNOH) 

Amido-cyanate  do.  do. 

Pseudo-uric  acid 

Baeyer  has  also  given  us  an  explanation  of  another 
group  of  compounds,  viz.  alloxantine,  hydurilic  acid 
(cf.  above,  p.  94),  and  violantine.  Alloxantine  is 
formed  from  a  molecule  each  of  alloxan  and  dialuric 
acids  by  loss  of  two  molecules  of  water  : 

N2C408H2(OH)2+N2C408H3(OH)  =  N2C403H2-O-N2C4O3H2 

+  2H20 

Hydurilic  acid  is  formed  similarly  from  dialuric  and 
barbituric  acids,  by  loss  of  only  one  molecule  of 
water  : 

N2C408H8(OH)+N2C40SH4  =  N2C408H8-N2C4O8Hs  +  H20 


THE   URIC  ACID  GROUP  97 

and  violantine  is  a  loose  molecular  combination  of 
violuric  and  dilituric  acids  : 

[N2C403H2(NOH)  +  N2C403H8(N02)] 

None  of  these  three  compounds  are  of  importance 
in  connection  with  the  constitution  of  uric  acid. 

Baeyer  concluded  his  investigations  with  the  syn- 
thesis of  hydanto'in,  one  of  the  oxidation  products 
of  uric  acid.  Monobromacetyl  urea  is  formed  by 
action  of  bromine  upon  acetyl  urea : 

NH-CO 

C0\  ^H2   JBr 

NH|, 


When  heated,  this  loses  hydrobromic  acid  as  indi- 
cated, and  hydantoin  is  formed  : 


NH-CO 


xl^ii \J\J 

\NH-CH2 


and  is  thus  shown  to  be  glycolyl  urea.     It  may  be 
regarded  as  a  reduction  product  of  parabanic  acid 

or  oxalyl  urea  : 

/NH-CO 
COc  I 

\NH-CO 

In  the  meantime,  a  number  of  other  natural  prod- 
ucts were  being  brought  into  connection  with  uric 
acid.  In  particular,  it  was  suspected  that  guanine 
and  xanthine  were  related  to  uric  acid,  owing  to  the 
similarity  in  composition : 

C6H4N408,  uric  acid 
CgHsNsO,  guanine 
C6H4N402,  xanthine 


98          THE  SPIRIT  OF  ORGANIC  CHEMISTEY 

No  facts  were  known  which  directly  proved  any  con- 
sanguinity between  these  three  substances.  In  1859, 
Strecker1  succeeded  in  converting  guanine  into 
xanthine  by  means  of  nitrous  acid  : 

C5H6N60  +  HN02  ==  C6H4N402  +  N2  +  H20 

The  formulae  of  the  two  compounds  could  therefore 
be  resolved : 

C6H3N40  (NH2)  C6H3N40  (OH) 

Guanine  Xanthine 

Two  years  later,2  he  offered  an  explanation  of  the 
relationship  of  xanthine,  theobromine,  and  caffeine. 
Theobromine  was  to  be  regarded  as  dimethyl-,  caf- 
feine as  trimethylxanthine  : 

C6H2N402(CH3)2  C6HN402(CH3)3 

Theobromine  Caffeine 

Strecker  partially  proved  this  view  by  directly  con- 
verting theobromine  into  caffeine  ;  an  attempt  to 
prepare  the  former  from  xanthine  failed.  Strecker 
had  not  erred,  however  ;  for  many  years  later  E. 
Fischer 3  was  able  to  effect  the  transition  by  a  slight 
modification  of  Strecker's  method. 

No  notable  advance  in  the  history  of  uric  acid 
occurred  until  1875,  when  Medicus  suggested  series 
of  structural  formulse  for  the  whole  group  of  sub- 
stances. Curiously  enough,  though  advanced  upon 
evidence  hardly  worth  the  name,  these  f ormula3  have 
constituted  the  centre  of  discussion  throughout  the 

1  Ann.  Chem.  (Liebig),  108,  141  (1859). 

2  Ibid.  118,  170  (1861).  8  Ibid.  215,  253  (1882). 


THE  URIC  ACID   GROUP  99 

subsequent  development  of  this  complicated  branch 
of  structural  chemistry. 

Medicus  1  proposed  the  following  constitution  for 

uric  acid  : 

NH-CO 

CO/          C-NH, 
\          II  >CO 

NH-C-NH/ 

His  reasons,  briefly  stated,  were  first  that  heating 
with  acids  gives  glycocoll  (amidoacetic  acid),  ammo- 
nia and  carbonic  acid;  secondly,  that  as  shown  by 
Liebig  and  Wohler,  alloxan  and  urea  are  formed  upon 
oxidation  ;  and  thirdly,  that  oxidation  with  potas- 
sium permanganate  (in  alkaline  solution)  gives  allan- 
toin,2  which  readily  passes  into  urea  and  glyoxylic 
acid. 

Led  on  by  the  supposed  close  relation  between 
uric  acid  and  the  substances  just  mentioned,  Medicus 
ascribed  similar  structures  to  xanthine,  guanine,  etc. 


Xanthine 


(CH8)N-CO 
Theobromine  CO<          C-NH 

VH 

Ui 


*  Ann.  Chem.  (Liebig),  175,  236  (1875). 

2  Allantoin  probably  possesses  the  following  structure  : 

/NH-CH-NHv 

C0<  >CO 

\NH-CO  NH2' 

viz.  a  di-ureid  of  glyoxylic  acid. 


100        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

(CH3)N-CO 

Caffeine  CO/        C-N(CH3)       - 

\        II         \ntr 


NH-CO 
Guanine  NH=C<  C-NH 

\  I'         \ 


NH-CO 
Hypoxanthine          CH/  C-NH 

\  II 

x  X  -  C  - 


For  these  formulae  absolutely  no  experimental  evi- 
dence was  adduced.  This  was  of  minor  importance, 
however,  since  none  of  Medicus's  proposals  attracted 
attention.  For  uric  acid,  indeed,  popular  choice 
favored  a  formula  advocated  by  Fittig  in  his  well- 

known  text-book  :  1 

NH-C-NH 


Again  the  prosecution  of  the  problem  came  to  a 
standstill  for  a  considerable  period.  In  1882,  how- 
ever, an  elaborate  experimental  investigation  of  caf- 
feine was  published  ;  the  name  of  its  author  —  Emil 
Fischer — guaranteed  its  contents.2  Fischer's  reason 
for  attacking  this  substance  first  seems  to  have  been 
the  hope  of  finding  a  pathway  to  it  from  uric  acid. 
At  any  rate,  it  was  not  hard  (for  Fischer)  to 
unravel  the  structure  of  caffeine,  and  subsequently 
to  apply  his  new  experiences  to  uric  acid  itself. 

1  Grundriss  der  Organ.  Chem.  10th  edition,  p.  309. 

2  Ann.  Chem.  (Liebig),  215,  253  (1882).  -  .  ^ 


THE  UEIC  ACID  GROUP  101 

The  following  facts  give  the  key  to  Fischer's 
caffeine  formula  : 

(CH8)N-CH 

II 

C-N(CHg) 
I      >CO 

-C=N 

a  formula  differing  but  slightly  from  that  given  by 
Medicus.  In  the  first  place,  treatment  of  caffeine 
with  chlorine  in  water  solution  yields  dimethyl- 
alloxan  and  monomethyl-uiea,  (a  process  of  simul- 
taneous oxidation  and  hydrolysis).  Therefore  nine 
of  the  ten  hydrogen  atoms  in  caffeine  occur  in  the 
form  of  three  methyl  groups. 

Secondly,  the  tenth  hydrogen  atom  may  be  directly 
replaced  by  chlorine  or  bromine  (forming  chlor-  or 
brom-caffeine).  On  heating  bromcaffeme  with  am- 
monia we  can  get  amno-caffeme,  with  caustic  potash 
hydroxy -caffeine. 

In  the  third  place,  hydroxycaffeine  contains  a 
double  bond  somewhere  among  its  carbon  atoms. 
We  know  this  because  it  takes  up  a  molecule  of 
bromine,  and  because  further  the-  bromine  atoms 
thus  added  may  be  exchanged  for  ethoxyl  groups 
(OC2H5),  by  the  simple  action  of  alcohol.  The  re- 
sulting product  is  called  di-ethoxy -hydroxycaffeine. 

Fourthly,  diethoxyhydroxycaffeine  is  easily  con- 
verted into  caffuric  acid.  The  first  step  consists  in 
eliminating  one  molecule  of  methylamine  and  two  of 
alcohol  by  boiling  with  concentrated  hydrochloric 
acid,  whereby  a  substance  called  apocaffeine  is  formed. 
Apocaffeine  loses  carbon  dioxide  when  boiled  with 
water,  and  passes  into  caffuric  acid.  Caffuric  acid 
may  also  be  obtained  by  moderately  oxidizing  caf- 


102        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

feine  itself  with  chlorine.  Caffuric  acid,  on  its  part, 
may  be  hydroly zed l  into  mesoxalic  acid,  methylamine, 
and  monomethylurea. 

Reducing  agents,  e.g.  hydriodic  acid,  abstract  an 
oxygen  atom  from  caffuric  acid,  forming  hydrov&i- 
f  uric  acid,  which  is  thus  the  corresponding  derivative 
of  tartronic  acid.  Hydrocaffuric  acid  is  decomposed 
on  boiling  with  barium  hydroxide,  yielding  methyl- 
amine, carbon  dioxide,  and  methylhydanto'in.  The 
monomethyl-urea  residue  of  caffeine  is  therefore 
united  to  the  rest  of  the  molecule  in  the  following 

manner  : 

-C-N(CH3) 
I        >CO 
-C-N 

this  being  the  skeleton  of  methylhydantoin  (cf. 
p.  97).  This  is  one  of  the  most  important  data  in 
fixing  upon  the  final  structure  of  caffeine. 

A  sixth  link  in  the  chain  starts  from  diethoxy- 
hydroxycaffeme.  When  this  substance  is  decomposed 
with  hydrochloric  acid,  the  substance  %£>ocaffeine 
accompanies  the  main  product  apocaffeme.  Hypo- 
caffeine  differs  from  the  latter  in  its  composition  by 
a  molecule  of  carbon  dioxide.  It  loses  carbon  diox- 
ide on  boiling  with  bases,  and  is  converted  in  caffo- 
line.  One  of  the  oxidation  products  of  this  substance 
is  dimethyloxamide,  which  contains  its  methylamine 
groups  attached  to  two  adjacent  carbon  atoms.  Two 
formulae  are  thereby  made  possible  for  caffoline : 

L  N(CH8)  II.       HO.HC-N(CH8) 

CH/>0  I       >° 

I    \/  (CH8)NH-C=N 

(CH«)NH-CO    NH  (1) 

1  With  basic  lead  acetate. 


THE  URIC  ACID  GROUP  103 


These  formulae  differ  in  the  manner  in  which  nitro- 
gen atom  (1)  is  attached  to  the  rest  of  the  molecule. 
But  I.  is  excluded  because  of  the  close  relation  of 
caffoline  to  hydrocaffuric  acid,  which  latter  we  have 
just  seen  to  contain  the  grouping  II. 

Fischer  combines  all  of  these  rather  complicated 
facts  into  the  caffeine  formula  already  given.  It 
will  suffice  for  our  present  purposes  to  append  the 
corresponding  structure  of  hydroxyeaffeme  : 

(CH3)N-C-OH 

/       'I 
CO/          C-N(CH)8 

(CH3)N-C=N/CO 

Since  we  know  caffeine  to  be  fH-methylxanthine 
(p.  98),  it  is  not  difficult  to  formulate  the  mother- 
substance  xanthine  : 


(a)  NH-CH 
II 
C-NH  (c) 

(6)  NH-C=1 


CO/ 


Theobromine  is  dimethylxanthine ;  as  three  places 
are  open  to  occupation  by  but  two  alkyl  radicals,  it 
becomes  necessary  to  determine  their  relative  posi- 
tion. One  methyl  group  is  located  in  (<?),  for  oxida- 
tion of  theobromine  gives  methylurea.  The  other 
methyl  occurs  at  (a) ;  because  if  we  replace  the  re- 
maining imide  h}rdrogen  by  an  ethyl  radical,  we 
obtain  homologous  apo-  and  hypo-caffeines  (ethyl- 
theobromine  derivatives).  In  all  of  the  above  meta- 
morphoses of  the  caffeine  molecule,  the  methyl  group 
at  (6)  retains  its  place  ;  as  the  ethyl  group  does 


104       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

likewise  in  ethyl-theobromine,  the  second  methyl  in 
theobromine  must  be  attached  to  nitrogen  atom  (a). 
The  investigation  of  uric  acid  —  in  particular  the 
establishment  of  a  genetic  connection  between  this 
substance  and  the  xanthine  series  —  next  engaged 
Fischer's  attention.  The  action  of  phosphorus  penta- 
chloride  upon  monomethyl-uric  acid  furnishes  two 

new  substances  : 

CH3.C5N4(OH).C12 

CH3.CSN4.C13 

formed  by  replacement  of  two,  respectively  three 
hydroxyl  groups  in  the  mother-substance  by  chlo- 
rine. These  halogen  derivatives  manifest  a  number 
of  reactions  in  which  the  chlorine  atoms  are  replace- 
able. The  resulting  products,  which  need  not  occupy 
our  attention  here,  may  all  be  regarded  as  substitu- 
tion-products of  a  compound  (CH3)C5N4H3,  which 
Fischer  calls  methylpurin.  Henceforth,  all  the 
various  substances  derived  from  or  related  to  uric 
acid  may  be  considered  purin  derivatives  : 


purn 

C5N4H4O3,     trioxy-purin,  uric  acid 
CH3  .  C5N4H3O3,     trioxymethyl-purin,  methyluric  acid 
(CH3)2C5N4H203,    trioxydimethyl-purin,  dimethyluric  acid 

The  chlorine  compounds  above  are  known  as  dichlor- 
oxy-methyl-purin  and  trichlor-methyl-purin  respec- 
tively. The  importance  of  the  purin  series  will 
appear  subsequently. 

The  investigation  of  the  various  methyl-uric  acids 
soon  demonstrated  the  untenability  of  Fittig's  for- 
mula (p.  100).  The  existence  of  a  tetramethyl-uric 
acid,  indeed,  proved  the  presence  of  four  imide 
groups  in  the  acid  ;  but  the  two  urea  residues  are  not 


THE  URIC  ACID   GROUP  105 

symmetrically  arranged,  and  so  Fittig's  structure 
falls  to  the  ground.  In  the  first  place,  two1  iso- 
meric  w0w0-inethyluric  acids  exist ;  one  of  these  may 
be  oxidized  to  alloxan  and  methyl-urea,  the  other  to 
methyl-alloxan  and  urea.  This  shows  that  the  former 
is  methylated  outside  the  alloxan  ring,  an  impossi- 
bility under  Fittig's  conception.  In  the  second 
place,  the  four  methyl  groups  in  tetramethyluric 
acid  are  attached  to  nitrogen,  because  hydrolysis  of 
this  substance  yields  methylamine  and  no  ammo- 
nia. And  thirdly,  the  oxidation  of  dimethyluric 
acid  produces  cholestrophan  (dimethyl-parabanic 
acid),  which  in  its  turn  is  an  oxidation  product  of 
dimethylalloxan.  Since  the  two  methyl  groups  in 
this  dimethyluric  acid  thus  turn  up  in  the  alloxan 
ring,  the  remaining  imide  groups  are  outside  of  this 
ring.  These  various  facts  lead  conclusively  to  the 
formula  for  uric  acid  originally  proposed  by  Medicus  : 
NH-CO 

C0<  C-NHv 

\          II  >CO 

NH-C-NH/ 

Uric  acid  may  thus  be  looked  upon  as  a  di-ureid 
of  (condensation  product  of  two  molecules  of  urea 
with)  trioxy-acrylic  acid : 

HO -CO 

C-OH 
II 
HO-C-OH 

This  acid  is  as  yet  unknown;   but  the  knowledge 
that  it  forms  the  skeleton  of  uric  acid  made  the 

1  Four  are  theoretically  conceivable.  They  are  all  known.  Cf. 
v.  Loeben,  Ann.  Chem.  (Liebig),  298, 181  (1897). 


106        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

synthesis  of  that  substance  a  concrete  possibility. 
And  so  the  attempts  to  artificially  prepare  this  com- 
plicated compound  form  the  logical  as  well  as  the 
historical  sequence  of  Fischer's  analytic  triumphs. 

In  part,  the  synthesis  of  uric  acid  antedates  the 
investigations  we  have  just  scrutinized.  Horba- 
czewski,1  in  1882,  had  succeeded  in  obtaining  very 
small  quantities  of  this  substance  by  heating  urea 
with  glycocoll  (amido-acetic  acid).  The  mechanism 
of  the  reaction  is  by  no  means  clear,  and  the  amount 
of  uric  acid  it  furnishes  decidedly  unsatisfactory. 
But  by  taking  into  account  the  relation  of  the  com- 
pound to  dioxyacrylic  acid,  and  heating  the  very 
similar  substance  trichlor-lactic  acid  : 2 

HO -CO 
H-C-OH 

C1-C-C1 

Cl 

with  urea,  the  yield  of  the  desired  substance  was 
considerably  increased. 

We  owe  a  much  more  complicated,  but  much  more 
important,  synthesis  of  uric  acid  to  Behrend.3  When 
urea  and  acetoacetic  e&er  are  condensed,  the  first 
product,  uramidocrotonic  ester : 

NH-C-CH8 

/          l! 
CO/  CH 

NH2   C02.C2H6 

1  Monatsh.  1882,  796  ;  1885,  356. 

» Ibid.  1887,201,584. 

*Ann.  Chem.  (Liebig),  229,  1  (1885). 


THE   URIC  ACID   GROUP  107 

loses  alcohol  upon  saponification  and  forms  a  sub- 
stance called  methyl-uracil  : 

NH-C-CHg 

/"I l~\  S  ^Vv/"1  TT 

C°\  >CH 

NH-dO 

It  is  the  methyl  derivative  of  the  hypothetical  com- 
pound uracil : 

NH-CH 


which  Behrend  assumes  to  be  the  mother-substance 
of  this  series.  Strong  nitric  acid  attacks  methyl- 
uracil  ;  a  nitro  group  is  introduced,  and  the  methyl 
group  becomes  oxidized  to  carboxyl : 

NH-C-COOH 
!-NO2 


CO/  \C 

NH-dO 


forming  nitro-uracil  carboxylic  acid.  This  loses 
carbon  dioxide  when  boiled  with  water,  forming 
nitro-uracil : 

NH-CH 

CO/  %C-NOa 

NH-dO 

Reducing  agents  convert  this  substance  into  the  cor- 
responding amido-uracil,  but  as  a  rule  the  reaction 
does  not  stop  there ;  the  amido  group  is  replaced  by 
hydroxyl,  and  oxy-uracil  results  : 

NH-CH 

\C-OH 


<     > 

NH-CO 


108       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Another  formula  is  possible  for  this  substance,  tauto- 
meric  with  the  one  given,  but  the  reactions  of 
oxyuracil  render  it  less  likely  than  the  former. 
Oxyuracil  is  isomeric  with  barbituric  acid,  and  may 
thus  be  called  isobarbituric  acid. 

Isobarbituric  acid  proved  rather  an  impassable 
barrier;  and  it  was  not  until  four  years1  later  that 
Behrend  was  able  to  surmount  the  innumerable 
obstacles  which  blocked  the  way  to  his  goal.  Oxida- 
tion of  oxyuracil  (bromine  water  was  the  reagent 
which  made  this  operation  feasible)  leads  to 
uracil  or  isodialuric  acid : 


< 


NH-C-OH 
C-OH 
NH-( 


And  this,  finally,  condenses  with  urea  to  yield  the 
long-sought  uric  acid : 


co< 

NH-C- 

/                     II 

v               1 

OH 

i 
OH 

Hf'NH 
h       i    >CO 

Hf'NH    =  CC 

NH-C-NH 
/           II         >CO 
)/            C-NH  +  2H20 

N.                        1 

NH-CO 

NH-CO 

An  elaborate  comparison  of  synthetic  uric  acid  with 
the  natural  substance  proved  the  complete  identity 
of  the  two. 

This  is  where  the  history  of  uric  acid  stands  to-day, 
or  rather,  stood  yesterday.  The  various  text-books 
of  organic  chemistry  more  or  less  completely  outline 
our  subject,  as  we  have  just  seen  it.  But  science 
makes  rapid  strides,  and  here,  as  elsewhere,  has  out- 

1  Ann.  Chem.  (Liebig),  251,  235  (1888). 


THE   URIC  ACID  GROUP  109 

stripped  the  photographer  with  his  cumbersome  text- 
book camera.  And  so  it  has  come  to  pass  that  the 
man  who  has  taught  us  so  much  is  now  teaching  us 
more.  Fischer's  syntheses  in  the  uric  acid  group 
have  led  him  to  revise  a  considerable  portion  of  his 
previous  doctrines. 

His  first  work  in  this  new  direction  was  a  syn- 
thesis of  uric  acid  itself.  This  is  hardly  the  place 
for  personal  comments,  but  it  seems  characteristic 
of  many  of  Fischer's  achievements  that  he  succeeds 
where  others  have  tried  and  failed  ;  and  the  admira- 
tion which  this  success  commands  is  but  heightened 
by  the  names  of  his  predecessors.  Liebig  and  Wohler 
had  correctly  surmised  the  relation  of  uramil  to  uric 
acid ;  but  their  efforts  to  unite  uramil  and  cyanic 
acid  proved  abortive.  Baeyer,  by  a  slight  modifi- 
cation of  their  method,  effected  this  union ;  but  he 
was  unable  to  dehydrate  the  resulting  pseudo-uric 
acid.  Fischer  found  the  missing  reagent ;  pseudo- 
uric  acid  gives  up  a  molecule  of  water  to  molten 
oxalic  acid,1  and  the  dreams  of  Liebig,  Wohler,  and 
Baeyer  are  realized.  It  should  be  pointed  out  that 
this  new  synthesis  is  simpler  than  the  older  ones, 
and  that  above  all  it  is  available  for  the  syntheses 
of  numerous  homologous  derivatives.  I IVIaTohic^acid" 
condenses  with  urea  and  forms  barbituric  acid.  Bar- 
bituric acid  is  converted  into  violuric  acid  by  nitrous 
acid.  Reduction  of  violuric  acid  leads  to  uramil. 
Uramil  and  potassium  cyanate  yield  pseudo-uric  acid. 
And,  finally,  pseudo-uric  acid  loses  water  and  forms 
uric  acid  itself.  It  will  be  readily  seen  that  by  em- 

1  Ber.  d.  chem.  Gesell.  28,  2473  (1896). 


110        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

ploying  substituted  ureas  in  the  above  series,  substi- 
tuted uric  acids  are  obtainable. 

Once  the  conversion  of  pseudo-uric  acid  was  proved 
possible  it  did  not  take  Fischer  long  to  find  an  easier 
method ;  the  dehydration  occurs  on  simple  boiling 
with  dilute  mineral  acids.1  The  application  of  this 
simple  process  to  some  methyl-pseudo-uric  acids  has 
led  to  startling  results.  But  first  a  word  about  the 
nomenclature  of  these  substances.  Wherever  syn- 
thetic chemistry  obtains  a  foothold,  ordinary  methods 
of  naming  compounds  soon  prove  inadequate  and 
confusing.  Fischer  proposes  2  to  base  all  names  upon 
the  fundamental  purin  nucleus  which  he  employed 
years  ago  (cf.  p.  104).  The  nine  atoms  of  this 
nucleus  are  to  be  numbered  thus : 


1N--C6 

2C     5C--N7 

3N C N9 


C8 


and  the  place  of  the  substituents  indicated  by  placing 
the  proper  number  before  them. 

When  1,  3,  7-trimethylpseudo-uric  acid  : 

CHs-N-CO    CH3 

CH-N-CO-NH2 
CHS-N-CO 

is  dehydrated  with  dilute  hydrochloric  acid,  the 
resulting  trimethyluric  acid  proves  to  be  identical 
with  hydroxy  caffeine.  It  will  be  remembered  that 

1  Eer.  d.  chem.  Gesell  30,  559  (1897).  2  Ibid.  p.  557. 


THE   URIC  ACID  GROUP  111 

Fischer  had  come  to  the  conclusion  that  xanthine  and 
uric  acid  contained  different  carbon  chains.  Here 
was  a  surprisingly  close  relation  between  caffeine,  a 
simple  xanthine  homologue,  and  trimethyluric  acid, 
standing  in  a  similar  position  to  uric  acid.  If  any 
doubts  remained  in  Fischer's  mind,  they  were  speed- 
ily relieved  by  the  discovery  that  direct  alkylation 
converts  hydroxycaffeme  into  tetramethyluric  acid. 
And,  finally,  it  is  possible  directly  to  prepare  hy- 
droxycaffeme  by  methylating  uric  acid. 

Hydroxycaffeine,  then,  is  trimethyluric  acid,  and 
the  former  conclusions  must  be  revised  upon  the 
basis  of  its  new  formula  : 

CH3-N-CO 

CO/       C-N-CHs 

\       II      >CO 
CHs-N-C-NH 

Caffeine,  xanthine,  and  guanine  can  no  longer  be  con- 
strued as  before  ;  the  best  expression  of  their  behav- 
ior is  given  by  the  structures  proposed  by  Medicus, 
but  heretofore  discredited  upon  Fischer's  authority  : 

CH3.N-CO 


Caffeine  CO  C-N-CH8 


C-N- 


NH-CO 
Xanthine  CO  C-NH 


CO/  C- 

N  II 


NH-CO 

Guanine  NH  =  C  C-NH 


112       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

The  formula  of  theobromine  is  rendered  uncertain ; 
to  be  sure,  one  methyl  group  is  attached  to  the  hy- 
dantoin  complex,  but  the  position  of  the  other  in  the 
alloxan  ring  must  be  determined  afresh  (cf.  below). 

The  old  question  of  effecting  a  transition  from 
uric  acid  to  xanthine  thus  finds  a  simple  solution. 
Historically,  however,  it  had  been  accomplished  two 
years  previously  by  Fischer,1  during  the  course  of 
the  synthesis  of  caffeine.  1,  3-dimethyluric  acid 
passes  into  chlor-theophyllin  when  treated  with  phos- 
phorus pentachloride,  and  reduction  of  the  latter 
leads  to  iheophyUin,  which  is  1,  3-dimethylxanthine : 

CH3-N-CO                    CHg-N-CO                 .        CHS-N-CO 
CO/         C-NH    ^-CO/        C-NH       ^  CO/       C-NH 

\  \PO  >  ''  \P       PI  \  II  N 

PITT         \r      C*       TVTTT  /^v-'        /"'TT         \T       P       XT  //  PTT         XT       i~       --     - 

Lyil3 — JN — \s  —  .iM il  /  v/ils  —  -»M — \j  —  ±*/y  v^Ug  —  IN — ' 

1,  3-diinethyluric  acid.  Chlortheophyllin.  Theophyllin. 

Methylation  of  theophyllin2  leads  to  caffeine,  and 
thus  a  complete  synthesis  of  the  latter  is  achieved. 

But  to  recount  the  work  of  the  last  two  years 
would  need  a  volume  by  itself.  It  must  suffice  here 
to  briefly  mention  a  few  of  the  more  important  facts 
—  indeed,  as  yet  we  have  not  enough  perspective  to 
measure  their  full  value.  Complete  syntheses  are 
at  hand  for  xanthine,3  guanine,  and  a  number  of 
related  substances ;  adenin,4  a  decomposition  product 
of  nucleines,  hypoxanthine,  a  similar  substance  oc- 
curring in  extract  of  meat,  and  hetero-  and  para- 

1  Ber.  d.  Chem.  Gesell.  28,  3135  (1895). 

2  Kossel,  Ztschr.  physiol.  Chem.  13,  305  (1889). 

3  Ber.  d.  Chem.  Gesell.  30,  2226  (1897). 

4  Ibid.  31,  104  (1898). 


THE  URIC  ACID  GROUP  113 

xanthine,1  isomeric  mono-methyl  xanthines  of  some 
physiological  importance.  Theobromine,  too,  has 
been  prepared  synthetically  from  3,  7 -dimethyl- 
pseudo-uric  acid,2  and  is  therefore  3,  7-dimethyl- 

xanthine : 

NH-CO 

C-N-CHg 


CO/ 


instead  of  1,  7-dimethylxanthine  as  heretofore. 

The  satisfactory  resolution  of  the  uric  acid  group 
closes  one  of  the  most  noteworthy  chapters  in  the 
history  of  chemistry.  It  is  difficult  to  estimate  the 
full  significance  of  this  work,  or  to  set  a  limit  to  its 
value  for  the  physiology  of  the  future.  It  is  clear 
that  an  adequate  comprehension  of  cellular  processes 
in  the  human  body  must  wait  upon  thorough  chem- 
ical knowledge  of  the  products  of  cellular  activity. 
The  inspiring  nature  of  this  chemical  problem  can- 
not be  better  exemplified  than  by  appending  the 
names  of  those  who  have  given  their  best  thoughts 
to  it  —  Liebig,  Wohler,  Baeyer,  Emil*Fischer. 

1  Ser.  d.  Chem.  Gesell  30,  2400  (1897). 

2  Ibid.  30,  1839  (1897). 

i 


CHAPTER  VI 
THE  CONSTITUTION  OF  THE  SUGARS 

THE  great  family  of  the  sugars,  starches,  cellu- 
loses, and  gums,  familiarly  known  as  the  carbo- 
hydrates, constitutes  one  of  the  earliest  recognized 
and  most  important  groups  of  organic  substances. 
They  play  a  decisive  part  in  the  animal  and  vege- 
table organism,  forming  a  large  portion  of  its  food 
and  its  tissues.  More  capital  and  labor  are  involved 
in  their  production  and  application  than  in  any  other 
branch  of  chemical  technology ;  it  is  only  necessary 
to  refer  to  the  manufacture  of  cane  and  beet  sugar, 
of  starch,  of  fermented  liquors,  of  paper  and  other 
cellulose  preparations,  and  to  the  distillation  of 
wood.  The  amount  of  work  devoted  to  the  chemi- 
cal investigation  of  the  carbohydrates  is  commen- 
surate with  this  importance.  The  literature  of 
organic  chemistry  contains  innumerable  treatises  on 
the  behavior  and  constitution  of  individual  mem- 
bers of  the  series.  But  the  actual  contribution 
toward  a  systematic  knowledge  of  composition  and 
constitution,  of  genetic  relations  among  and  syn- 
thetic preparation  of  these  compounds,  daring  the 
first  eighty-odd  years  of  the  century,  is  very  small 
indeed.  It  is  due  to  the  efforts  of  two  men,  H. 
Kiliani  and  Emil  Fischer,  that  the  former  chaos  of 
isolated  facts  has  become  one  of  the  most  beautifully 
organized  chapters  of  science.  Step  by  step,  the 

114 


THE  CONSTITUTION  OF  THE  SUGARS        115 

structure  of  these  substances  has  been  unravelled; 
and  step  by  step,  they  have  been  built  up  from  the 
simplest  of  materials  to  the  full  complexity  of  grape- 
sugar  and  its  congeners.  Not  only  have  we  learned 
the  inner  anatomy  of  Nature's  products,  but  numer- 
ous new  carbohydrates  have  been  added  to  the  list 
until  to-day  their  number  is  legion.  If  less  than 
ten  years  have  witnessed  the  complete  subjugation 
of  the  sugars  to  order  and  system,  what  may  we 
not  hopefully  look  for  in  Nature's  box  of  mysteries  ? 
The  first  attempt  to  give  a  precise  constitution 
to  a  particular  sugar  was  made  by  Baeyer.1  This 
sugar  was  the  so-called  methylenitane,  discovered  by 
Butlerow.2  The  fact  that  the  composition  of  the 
ordinary  sugars  was  expressed  by  the  formula : 
C6H12O6,  or  (C  — H2O)6,  naturally  suggested  that 
these  compounds  might  be  obtained  by  simple  poly- 
merization of  any  substance  possessing  the  compo- 
sition (CH2O)X;  such,  e.g.,  are  formaldehyde,  and 
its  polymer  trioxymethylene  (CH2O)3.  Butlerow 
found  that  by  adding  lime  water  to  trioxymethylene 
a  sweet  sugarlike  substance  was  formed,  to  which 
he  gave  the  name  methylenitane.  Baeyer  was  of 
the  opinion  that  its  formation  could  be  explained 
by  simple  condensation  of  six  molecules  of  formal- 
dehyde, thus : 

1      .  2          i  3          f          4          ;  5          i  6 

CH20  |  H-CHO  i  H-CHO  j  H-CHO  !  H-CHO  j  H-CHO 

i  !  !  !  i 

and  that  we  could  therefore  comprehend  the  process 
by  which  sugars  are  prepared  in  the  plants  them- 

i  Ber.  d.  chem.  Gesell  3,  66  (1870).  V 

*Ann.  Chem.  (Liebig),  120,  295  (1861). 


116        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

selves,  since  formaldehyde  might  readily  be  produced 
by  the  reduction  of  carbon  dioxide  by  chlorophyll. 

From  this  time  on  until  Kiliani's  demonstration 
of  the  actual  constitution  of  several  sugars,  no  work 
of  very  great  importance  was  accomplished.  Fittig, 
in  a  theoretical  paper1  now  difficult  of  access,  pro- 
posed that  the  sugars  were  derivatives  of  hexane, 
C6H14,  viz.  aldehydes  of  the  various  possible  isomeric 
hexa-oxyhexanes.  This  view  was  the  subject  of 
much  discussion.  Whereas  no  serious  objections 
were  raised  to  Fittig's  formula  for  glucose,  as  the 
aldehyde  of  normal  mannite  (identical  with  Baeyer's 
formula  for  methylenitane),  Krusemann2  showed 
that  fructose  also  gave  mannite  on  reduction,  and 
therefore  also  contained  a  normal  chain.  Zincke3 
found  that  many  ketone-alcohols  gave  oxyacids  of 
the  same  number  of  carbon  atoms  when  oxidized, 
and  transferred  this  idea  to  the  sugars,  assigning 
the  following  formulse  : 

Glucose :     CH2OH-CHOH-CHOH-CHOH-CO-CH2OH 
Fructose :   CH2OH-CHOH-CHOH-CO-CHOH-CH2OH 

They  differ  in  the  position  given  the  carbonyl  group. 
This  view  was  adopted  by  Victor  Meyer,4  because  the 
sugars  did  not  give  a  certain  aldehyde  reaction,  viz. 
a  red  color  with  a  solution  of  fuchsine  decolorized 


1  Uber  die  Constitution  der  sogenannten  Kohlenhydrate  (Tu- 
bingen, 1871). 

2  Ber.  d.  chem.  Gesell.  9,  1465  (1876). 

»  I.e.  13,  641  (1880);  Ann.  Chem.  (Liebig),  216,  318  (1883). 
*  Ber.  d.  chem.  Gesell.  13,  2343  (1880);  Schmidt,  ibid.  14,  1860 
(1881). 


THE  CONSTITUTION   OF  THE  SUGARS        117 

with  sulfurous  acid.1  The  preparation  of  oximes2 
of  the  sugars  by  the  action  of  hydroxylamine,  showed 
that  they  must  be  either  aldehydes  or  ketones. 

The  aldehyde  formula  for  glucose  was  greatly 
strengthened  by  the  fact  that  on  oxidation  it  fur- 
nished acids  of  the  same  number  of  carbon  atoms 
(gluconic  and  saccharic  acids),  though,  as  we  have 
seen  from  Zincke's  work,  this  did  not  preclude  a 
ketone  structure.  In  1880,  Kiliani3  showed  that 
fructose  gave  oxidation  products  containing  less  than 
six  atoms  of  carbon  ;  this,  in  conjunction  with  the 
formation  of  mannite  upon  reduction,  proved  fruc- 
tose to  be  a  ketone  with  normal  chain.  Four  j^ears 
later,  Kiliani  and  Kleemann4  proved  the  presence 
of  a  normal  chain  in  gluconic  acid,  the  only  previous 
demonstration  of  this  fact  being  the  oxidation  of 
gluconic  to  saccharic  acid  : 

HOOC-CHOH-CHOH-CHOH-CHOH-^COOH 
and  the  reduction  of  this  latter  to  adipic  acid  : 
COOH-CH2-CH2-CH2-CH2-COOH 

The  direct  reduction  of  gluconic  acid  gave  an  oxy- 
capronic  acid  : 


respectively  its  anhydride,  caprolactone. 

1  This  "  fuchsine-sulfurous  acid  reaction  "  has  since  then  always 
occupied  a  prominent  place  in  the  discussions  on  the  sugar  question, 
far  more  prominent  than  it  deserves  ;  for  its  mechanism  is  un- 
known, and  it  is  given  by  some  compounds  which  are  not  alde- 
hydes. No  diagnostic  value  is  at  present  attached  to  this  reaction. 

2V.  Meyer  and  Schulze,  Ber.  d.  chem.  Oesell.  17,  1654  (1884); 
Rischbieth,  ibid.  20,  2673  (1887);  Wohl,  ibid.  24,  993  (1891). 

8  Ann.  Chem.  (Liebig),  205,  190  (1880). 

*  Ber.  d.  chem.  Gesell.  17,  1296  (1884). 


118       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Kiliani  l  next  showed  that  the  product  obtained  by 
oxidation  of  galactose,  galactonic  acid,  is  a  normal- 
chain  acid  isomeric  with  gluconic  acid,  for  it  also 
yields  caprolactone  upon  reduction.  This  proved 
galactose  to  be  an  aldehyde  of  normal  hexa-oxyhex- 
ane,  just  as  glucose  is. 

The  chief  reaction  whereby  Kiliani  was  enabled  to 
establish  the  constitution  of  many  sugars  consisted 
in  the  application  of  a  well-known  and  simple  syn- 
thetic process.  Aldehydes,  as  well  as  ketones,  add 
hydrocyanic  acid  to  form  cyanhydrines, 


>C=0  +  HCN  = 


and  these  oxynitriles  are  readily  saponified  to  acids. 
Now,  if  the  sugars  are  aldehydes  or  ketones,  they 
should  add  hydrocyanic  acid,  and  the  structure  of 
the  acids  formed  from  these  will  show  what  the  con- 
stitution of  the  sugar  is.  Thus  glucose  2  was  found 
to  give  a  cyanhydrine  ;  the  acid  prepared  from  this, 
when  reduced,  yielded  normal  heptylic  acid  : 

1.  CH2OH-CHOH-CHOH-CHOH-CHOH-CHO 

2.  CH2OH-CHOH-CHOH-CHOH-CHOH-CH<£JJ 

^iM 

3.  CH2OH-CHOH-CHOH-CHOH-CHOH-CHOH-COOH 

4.  CH3-CH2-CH2-CH2-CH2-CH2-COOH 

This  proved  glucose  to  be  the  aldehyde  of  mannite  ; 
it  cannot  be  a  ketone.  Fructose,3  on  the  other  hand, 

1  Ber.  d.  chem.  Gesell.  18,  1555  (1885). 

2  Ibid.  19,  1128  (1880). 

8  Ibid.  23,  449  (1890);  Diill,  ibid.  24,  348  (1891). 


THE  CONSTITUTION  OF  THE  SUGAES        119 

gave  methyl-lutyl-acetic  acid,  which  can  be  explained 
only  as  follows  : 

1.  CH2OH-CHOH-CHOH-CHOH-CO-CH2OH 

2.  CH2OH-CHOH-CHOH-CHOH-C<°**-CH2OH 

3.  CH2OH  -  CHOH  -  CHOH  -  CHOH  -  C<  -  CH2OH 

4.  CH3-CH2-CH2 


Fructose  is  thus  a  ketone  of  mannite,  with  its  car- 
bonyl  in  ft  position. 

Kiliani  1  extended  his  work  to  arabinose,  a  sugar 
obtained  from  cherry  gum,  to  which  the  formula 
C6H12O6  had  been  given.  His  results  were  startling. 
In  the  first  place,  he  found  that  arabinose  furnished 
tetraoxyvalerianic  acid  when  oxidized;  i.e.  an  acid 
with  five  atoms  of  carbon.  The  hydrocyanic  acid 
addition  product  of  arabinose  treated  as  above  gave 
a  lactone  C6H10O6,  which  upon  reduction  was  con- 
verted into  caprolactone  resp.  caproic  acid.  Arabi- 
nose must  therefore  be  an  aldehyde,  as  it  is  a  normal 
derivative,  and  contains  only  five  atoms  of  carbon  in 
the  molecule;  its  formula  is  C6H10O6.  Upon  a 
reduction  it  yielded  a  new  alcohol,  arabite,  of  the 
composition  C5H12O5.  To-day,  when  we  know 
sugars  containing  from  three  to  nine  carbon  atoms, 
this  seems  of  no  great  import.  But  as  late  as  ten 
years  ago,  until  this  discovery  of  Kiliani's,  it  was 
axiomatic  among  chemists  that  all  carbohydrates 
contained  six  atoms  of  carbon  or  some  multiple 

thereof. 

is 

i  Ser.  d.  chem.  GesellsW,  3029  (1886);  20,  339  (1887);  20,  133 
(1887). 


120       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

These  memorable  researches  of  Kiliani  would  seem 
to  have  been  sufficient  for  all  purposes  of  constitutive 
and  synthetic  progress.  Glucose  was  shown  to  be 
the  aldehyde  of  mannite,  galactose  the  aldehyde  of 
an  isomere  of  mannite,  fructose  to  be  a  ketone 
derived  from  mannite,  containing  its  carbonyl  in  /3 
position,  arabinose  to  be  the  aldehyde  of  a  new 
penta-acid  alcohol  with  normal  chain.  Truly  re- 
markable results  for  a  few  years'  work.  But  why 
did  not  Kiliani  continue  in  the  path  he  had  followed 
with  such  success  ?  Why  was  it  left  for  another  to 
reap  the  harvest  ? 

Because  of  almost  insurmountable  experimental 
difficulties,  requiring  skill  and  patience  and  insight 
such  as  are  seldom  united  in  one  individual.  Even 
when  pure,  sugars  crystallize  with  difficulty ;  when 
mixtures  are  present,  when  other  organic  and  inor- 
ganic materials  are  formed  or  introduced  during  the 
reactions,  the  task  of  isolating  a  sugar  by  ordinary 
means  is  hopeless.  The  man  who  discovered  the 
magic  touchstone,  and  who  possessed  the  necessary 
skill  and  patience  and  insight,  was  Emil  Fischer ; 
his  wizard's  wand  was  phenylhydrazine.  Fischer's 
researches  on  the  sugars  date  from  1887,  and  are  laid 
down  in  innumerable  separate  articles.  Fortunately 
their  author  has  furnished  two  elaborate  resumes 1  of 
his  work,  to  which  the  reader  is  referred,  and  from 
which  the  following  brief  sketch  is  taken. 

As  is  well  known,  phenylhydrazine  reacts  readily 
with  carbonyl  groups : 

>CO  +  H2N-NHC6H5  =  >C=N-NHC6H5  +  H2O 
1  Ber.  d.  chem.  GeselL  23,  2114  (1890);  27,  3189  (1894). 


THE  CONSTITUTION  OF  THE  SUGARS        121 

A  condensation  of  this  base  with  the  sugars,  which 
we  have  found  to  contain  the  aldehyde  or  ketone 
grouping,  is  therefore  to  be  expected.  Fischer  found, 
however,  that  the  reaction  is  not  simple  in  this  case. 
For  although  the  first  step  proceeds  normally 

CH2OH-CHOH-CHOH-CHOH-CHOH-CH=N-NHC6H5 

to  form  a  hydrazone,  this  hydrazone  is  usually  easily 
soluble,  and  escapes  detection  ;  and,  furthermore,  it 
undergoes  a  very  peculiar  oxidation  when  warmed 
with  excess  of  the  hydrazine  base.  The  alcohol 
group  marked  with  a  *  in  the  above  formula  gives 
up  its  hydrogen  atoms  to  pass  into  the  carbonyl 
group  ,-  this,  then,  reacts  with  more  phenylhydrazine 
quite  normally,  producing  an  osazone : 

CH2OH-CHOH-CHOH-CHOH-C-CH  =  N-NHC6H6 

II 
N-NHC6H6 

The  hydrogen  atoms  which  leave  the  sugar  reduce 
a  molecule  of  phenylhydrazine  to  aniline  and  am- 
monia ;  the  complete  reaction  thus  requires  three 
molecules  of  the  base  to  one  of  sugar. 

These  osazones  possess  the  very  desirable  property 
of  being  quite  insoluble  in  water,  and  easily  crystal- 
lizable  from  other  solvents.  Thus  they  readily  serve 
to  detect  the  presence  of  sugars,  and  to  identify  them 
by  their  characteristic  melting  points.  It  was  by 
means  of  this  reaction  that  Fischer  was  able  to 
isolate  and  identify  his  synthetic  sugars.  It  is  a 
very  curious  fact,  however,  which  will  be  entered 
into  in  detail  farther  on,  that  several  sugars  give 
identical  osazones ;  thus,  glucose,  fructose,  and  man- 


122       THE  SPIRIT  OF  OEGANIC  CHEMISTRY 

nose  give  one  and  the  same  derivative,  viz.  glucosa- 
zone  (called  thus  because  first  obtained  from  glucose). 
The  reconversion  of  the  osazones  into  their  sugars 
is  a  difficult  task,  which  has  succeeded  but  imper- 
fectly. For  though  it  is  possible  to  split  off  the 
phenylhydrazine  group,  there  results  invariably  a 
ketose,1  whether  the  original  sugar  be  aldose  or  ketose. 
The  steps  of  the  reaction  are  as  follows :  First,  con- 
centrated hydrochloric  acid  replaces  the  hydrazone 
groups  with  oxygen  in  a  normal  manner : 

CH2OH-CHOH-CHOH-CHOH-C-CH=N-NHC6H6  +  2  H2O 

II 
N-NHC6H6 

=  CH2OH-CHOH-CHOH-CHOH-CO-CHO  +  2C6H5NH-NH2 

The  aldehyde-ketone  formed  is  called  an  osone;  no 
osones  have  yet  been  isolated  in  a  sufficiently  pure 
state  to  prove  the  formula  assigned  them,  but  their 
reactions  render  it  extremely  probable  that  the  as- 
sumption is  correct.  Secondly,  reduction  of  the 
osones  leads  to  ketoses,  by  a  simple  reaction. 

In  order  to  regenerate  an  aldose  from  an  osazone, 
it  is  necessary  to  reduce  the  ketose  first  obtained  to 
the  corresponding  alcohol,  which  then  upon  oxida- 
tion gives  an  aldose.2  It  is  easily  seen  that  the 
method  of  recovering  sugars  from  their  phenylhy- 
drazine compounds  is  far  from  satisfactory ;  it  is  re- 
sorted to  only  in  case  of  dire  necessity. 

The  goal  which  Fischer  set  for  himself  was  the 

1  Sugars  containing  an  aldehyde  group  are  called  aldoses,  e.g. 
glucose;  those  containing  a  ketone  group  are  called  ketoses ,  e.g. 
fructose. 

2  With  some  ketose  as  well. 


THE  CONSTITUTION  OF  THE  SUGARS        123 

synthetical  preparation  of  the  sugars,  a  problem  al- 
most as  old  as  the  science.  Let  us  follow  his  prog- 
ress, after  a  short  survey  of  the  previous  literature 
of  the  subject. 

The  formation  of  sugars  by  oxidation  of  the  poly- 
hydroxy-alcohols  had  been  first  observed  by  Carlet,1 
who  found  that  dulcite  behaved  thus ;  the  reaction 
was  then  studied  by  Gorup-Besanez  2  and  by  Daf ert,3 
who  showed  that  a  mixture  of  sugars  was  obtained 
here.  Van  Deen  *  showed  the  formation  of  a  sugar- 
like  substance  by  the  oxidation  of  glycerine,  a  fact 
rediscovered  by  Grimaux  5  much  later.  Fischer  was 
able  to  greatly  extend  this  chapter  by  proving :  first, 
that  the  oxidation  of  dulcite  gave  fructose  and  a 
new  sugar,  mannose ;  second,  that  Van  Deen's  reac- 
tion gave  a  real  sugar,  glycerose,  C3H6O3,  which, 
however,  is  a  mixture  of  the  two  possible  compounds, 
glycerine  aldehyde  and  dioxyacetone  : 

CH2OH-CHOH-CHO    and   CH2OH-CO-CH2OH 

and  third,  that  erythrite,  the  alcohol  with  four  atoms 
of  carbon,  also  gave  a  sugar,  erytlirose,  C4H8O4. 
Mannose  was  soon  thereafter  found  in  large  quanti- 
ties as  a  plant  product  in  the  so-called  reserve- 
cellulose. 

The  polymerization  of  formaldehyde  to  methyl- 
enitane  by  Butlerow  has  already  been  referred  to. 
This  was  the  first  real  synthesis  of  a  sugar,  though 

1  Jahresbericht,  1860,  250.  V 

2  Ann.  Chem.  (Liebig),  118,  257  (1861). 
»  Ber.  d.  chem.  Gesell.  17,  227  (1884). 

*  Jahresbericht,  1863,  501. 

5  Compt.  rend.  104,  1276  (1887). 


124       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

the  proof  of  this  came  much  later.  O.  Loew1 
(1886)  repeated  Butlerow's  work,  and  regarded  the 
sugar  he  obtained  as  different  from  methylenitane  ; 
he  called  it  formose.  Later2  he  succeeded  in  prepar- 
ing a  sugar  which  was  fermentable,  whereas  formose 
and  methylenitane  were  indifferent  toward  yeast; 
this  compound  he  called  methose. 

By  this  time  Fischer  had  already  begun  his  at- 
tempts to  synthesize  a  natural  sugar.  Acroleine 
di-bromide  is  converted  into  a  sugarlike  product 
by  alkalies  (best  barium  hydrate): 


2C8H4OBr2  +  2Ba(OH)2  =  C6Hi206  -f  2  BaBr2 

The  main  product  consisted  of  two  sugars,  which 
were  named  a-  and  ft-acrose.  Fischer  found  that 
a-acrose  was  present  in  small  quantity  in  methyleni- 
tane and  formose,  and  in  larger  quantity  in  methose, 
to  which  it  imparted  the  property  of  fermentability. 
What  made  a-acrose  especially  interesting,  however, 
was  the  remarkable  resemblance  between  its  osazone 
and  glucosazone;  they  differed  only  with  regard  to 
optical  activity,  a-acrosazone  being  inactive. 

The  evident  conclusion  to  draw  from  this  fact  was 
that  a-acrose  represented  the  inactive  modification  of 
either  glucose  or  fructose,  —  a  conclusion  borne  out 
by  subsequent  investigation.  The  chief  difficulty, 
of  course,  consisted  in  procuring  sufficient  material 
for  the  many  operations  required.  The  best  method 
of  preparing  a-acrose  was  found  to  consist  in  the 
polymerization  of  glycerose,  which  we  have  seen  to 

1  J.  prakt.  Chem.  [2]  33,  321  (1886). 

2  Ber.  d.  chem.  Gesell.  22,  475  (1889). 


THE  CONSTITUTION  OF  THE  SUGARS        125 

be  a  mixture  of  glyceric  aldehyde  and  dioxyacetone ; 
a  simple  "  aldol  condensation "  suffices  to  give  a 
sugar  of  the  same  structure  as  fructose  : 

CH2OH-CHOH-CHO  +  CH2OH-CO-CH2OH  = 
CH2OH-CHOH-CHOH-CHOH-CO-CH2OH 

The  yield  is  small,  as  a  number  of  other  products 
are  formed  at  the  same  time.  The  conversion  of 
a-acrosazone  into  its  sugar,  a-acrose,  was  carried  out 
by  means  of  the  above-described  process  (p.  122). 
a-Acrose  is  a  syrup  which  ferments  with  yeast,  gives 
levulinic  acid  when  heated  with  hydrochloric  acid, 
and  is  reduced  by  sodium-amalgam  to  a  new  hexa- 
oxyalcohol.  This  was  called  a-acrite,  and  closely 
resembles  mannite,  save  that  it  is  optically  inactive. 

But  by  the  time  a  kilo  of  glycerine  has  been  trans- 
formed into  a-acrite,  the  mass  has  shrunk  to  0.2 
gramme.  Small  hope  of  progress  by  this  road.  A 
series  of  fortunate  circumstances,  however,  supplied 
the  needed  links  in  the  chain. 

Mannose,  the  aldehyde  of  mannite,  may  be  readily 
oxidized  to  the  corresponding  mannonic  acid.  Owing 
to  the  difficulty  with  which  all  the  compounds  of  the 
sugar  group  crystallize,  this  acid  cannot  be  directly 
isolated;  but  phenylhydrazine  proved  its  efficacy  here 
by  forming  a  well-defined  hydrazide 1  of  the  acid : 

CH2OH-CHOH-CHOH-CHOH-CHOH-COOH  +  C6H6NH-]$H2  = 
CH2OH-CHOH-CHOH-CHOH-CHOH-CO-HN-NHC«H5+H20 

The  acid  is  easily  regenerated  from  this  hydrazide, 
and  obtained  in  the  form  of  its  lactone  C6H10O6.  It 

Y 
1  Just  as  ammonia  forms  an  amide,  or  aniline  an  anilide. 


126        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

will  be  remembered  that  the  lactone  obtained  by 
Kiliani  from  the  cyanhydrine  of  arabinose  also  pos- 
sessed this  composition.  A  comparison  of  the  two 
compounds  gave  the  remarkable  result  that  the  acids 
were  identical  in  every  respect  save  their  optical 
activity ;  Fischer's  lactone  turned  the  plane  to  the 
right,  Kiliani's  to  the  left.  In  aqueous  solution  they 
combined  to  form  a  third,  inactive,  substance. 

We  have  here  a  case  perfectly  similar  to  that  of 
dextro-  and  Isevo-tartaric  acid.  In  order  to  transfer 
these  conditions  to  mannose  itself,  we  need  but  to 
convert  the  lactones  into  their  corresponding  sugars. 
Now  it  is  well  known  that  the  reduction  of  an  acid 
to  its  aldehyde  or  alcohol  is  a  very  dubious  operation. 
Fischer  was  therefore  surprised  and  delighted  to  find 
that  the  lactones  are  reduced  to  aldehydes  with  ease 
and  despatch  on  being  treated  with  sodium  amalgam 
in  cold  acid  solution.  This  reaction,  simple  though 
it  is,  has  been  the  chief  factor  in  the  wonderful  de- 
velopment of  the  sugar  group.  Mannonic  acid  is 
thus  readily  reconverted  into  d-mannose ; 1  Kiliani's 
arabinose-carboxylic  acid  into  the  isomeric  1-mannose ; 
the  inactive  acid  into  i-mannose. 

These  sugars  may  be  reduced  to  their  alcohols, 
giving  three  optically  different  mannites.  Here  is 
where  the  sections  of  the  synthetic  chain  are  forged 
together  ;  for  i-mannite  is  identical  with  the  syn- 

1  The  prefixes  d-,  1-,  and  i-  denote  the  genetic  relations  of  these 
compounds,  and  not  the  actual  direction  in  which  they  rotate  the 
plane  of  polarized  light.  All  compounds  derived  from  ordinary 
(d-) glucose  are  therefore  d-compounds,  no  matter  what  the  nature 
of  their  optical  activity  is.  Thus,  d-glucosazone  rotates  to  the  left ; 
the  sugar  regenerated  from  it,  fructose,  also  rotates  to  the  left ;  but 
genetically  it  is  d-fructose. 


THE  CONSTITUTION   OF  THE  SUGABS        127 

thetic  a-acrite,  and  a-acrose  is  nothing  else  than 
i-fructose.  There  remains  only  to  pass  from  the 
inactive  series  to  the  active  in  order  to  complete  the 
synthesis  of  natural  sugars. 

For  this  purpose  we  possess  two  methods,  discov- 
ered by  Pasteur1  during  his  classic  research  on 
racemic  acid  :  partial  fermentation,  and  fractional 
crystallization  of  salts.  Only  the  former  method  is 
applicable  to  the  sugars.  a-Acrose  is  rapidly  at- 
tacked by  yeast ;  the  solution  is  no  longer  inactive, 
but  turns  the  polarized  plane  to  the  right  —  it  con- 
tains 1-fructose.2  Inactive  mannose  behaves  simi- 
larly ;  the  dextro  modification  is  destroyed,  the  laevo 
remains.  The  yeast  thus  feasts  upon  the  forms  it  is 
accustomed  to,  leaving  us  the  comparatively  uninter- 
esting optical  antimeres3  of  the  desired  compounds. 

Fischer  sought  refuge  in  chemical  methods.  i-Man- 
nite  was  oxidized  first  to  i-mannose,  then  to  i-man- 
nonic  acid.  The  fractional  crystallization  of  the 
strychnine  or  morphine  salts  of  this  last  furnished 
the  two  active  forms  of  mannonic  acid,  which  could 
then  be  reduced  to  the  corresponding*  sugars,  d-  and 
1-mannose.  d-Mannose  then  leads  to  d-fructose  by 
way  of  its  osazone,  since  mannose  and  fructose  give 
the  same  phenylhydrazine  derivative. 

Glucose  and  mannose  also  give  the  same  osazone. 
Their  difference  must  therefore  be  due  to  the  asym- 


1  Ann.  chim.  Phys.  (1848-1864). 

2  See  note  on  opposite  page. 

8  This  word  seems  to  be  better  adapted  for  general  use  than  the 
customary  "antipodes."  Its  meaning  is  quite  clear,  and  it  is 
used  throughout  this  book  to  express  optical  as  well  as  geometric 
isoinerism. 


128        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

metry  of  that  carbon  atom  which  in  the  osazone  is 
united  to  the  second  phenylhydrazine  group,  since 
identity  does  not  result  until  this  asymmetry  is 
destroyed  : 

CH2OH-CHOH-CHOH-CHOH-CHOH-CHO 

It  is  a  matter  of  general  experience  that  when  sub- 
stances containing  an  asymmetric  carbon  atom  are 
heated,  rearrangement  takes  place  so  as  to  form  the 
corresponding  antimeres.  E.g.  tartaric  acid  is  con- 
verted into  racemic  acid,  and  racemic  into  mesotar- 
taric  acid.  Since  glucose  and  mannose  differ  in  the 
spatial  grouping  around  just  one  carbon  atom,  a 
similar  readjustment  might  be  expected.  The  sugars 
themselves  are  too  unstable  for  such  treatment,  but 
their  acids  are  easily  convertible  —  best  when  heated 
with  quinoline  or  pyridine.  Thus  gluconic  acid  is 
partly  converted  into  mannonic  acid  when  heated  to 
140°  ;  mannonic  acid  is  similarly  transformed  into 
gluconic  acid,  a  condition  of  equilibrium  being 
reached.  As  d-gluconic  acid  is  easily  reduced  to 
d-glucose,  a  complete  synthesis  of  grape-sugar  has 
been  effected.  Chart  I.  will  show  this  in  detail,  to- 
gether with  the  synthesis  of  other  derivatives  of 
mannite. 

Fischer  was  able  to  go  farther  than  this,  however ; 
for  the  continuation  of  the  reactions  discovered  by 
Kiliani  and  himself  has  led  to  the  synthesis  of  sugars 
containing  more  than  six  atoms  of  carbon.  First  of 
all,  Fischer  found  that  the  addition  of  hydrocyanic 
acid  to  the  sugars  always  gives  two  stereo-isomeric 
acids;  thus  arabinose  yields  \-gluconic  acid  along 
with  the  1-mannonic  acid  discovered  by  Kiliani,  and 


THE  CONSTITUTION  OF  THE  SUGARS        129 


thereby  becomes  a  welcome  source  of  experimental 
material.  By  means  of  the  cyanhydrine  reaction  on 
the  hexoses,  and  reduction  of  the  resulting  acids  as 
described,  sugars  were  obtained  from  mannose  and 

CHART  I 


I.  fructose 


t .  mannonie  acid 

•  mannonie  acid 


d-mannose 


d-  saccharic  acid 


d  -  mannifo 


A-glttcosazone 

Y 
d  -fructose 


glucose  containing  seven  carbon  atoms.  These  hep- 
toses,  manno-heptose  and  gluco-heptose,  by  the  same 
methods  then  gave  corresponding  octoses  and  nonoses, 
the  latter  having  the 


CH2OH-CHOH-CHOH-CHOH-CHOH-CHOH-CHOH-CHOH-CTIO 

Were  it  not  that  by  the  time  these  nonoses  are 
reached,  the  supplies  of  material  have  dwindled 
down  to  microscopic  dimensions,  we  should  probably 
have  sugars  with  ten  and  twenty  carbon  atoms  in  a 
chain;  though  whether  the  sugars  would  be  any 
sweeter,  we  have  no  means  of  knowing. 


130       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

These  were  the  main  results  reached  by  Fischer 
at  the  time  of  his  lecture  before  the  "  Chemische 
Gesellschaft "  (1890).  The  mannite  group  lay  com- 
pletely unravelled  before  the  world.  Since  then,  the 
dulcite  and  sorbite  families  have  been  the  object  of 
care  and  attention,  with  considerable  success.  The 
most  important  problem,  however,  consisted  in  the 
determination  of  the  actual  space  configuration  be- 
longing to  the  various  sugars.  No  less  than  sixteen 
isomeric  hexoses  are  possible,  according  to  the  theory 
of  Le  Bel  and  van  t'Hoff,  which  possess  the  plane- 
structure  of  glucose.  Here,  too,  success  has  waited 
upon  the  efforts  of  the  pioneer  in  the  field,  for  no 
less  than  eleven  of  the  possible  sixteen  forms  are 
known  to-day. 

It  is  not  the  object  of  this  chapter  to  give  a  com- 
plete catalogue  of  all  the  compounds  of  the  sugar 
series,  nor  on  the  other  hand  to  deduce  and  prove 
the  phenomena  of  stereochemistry ;  we  can  therefore 
only  develop  the  configurations  of  the  hexoses,  and 
their  immediate  derivatives,  as  being  the  most  impor- 
tant, as  far  as  needed  for  this  purpose.  The  method 
of  formulating  the  asymmetry  of  carbon  atoms  is 
quite  simple.  If  we  imagine  the  carbon  tetrahedron  : 


projected   upon   the   plane  of  the   paper,  the   four 
valences  will  be  spread  out  as  follows  : 


THE  CONSTITUTION   OF  THE  SUGARS        131 


In  the  case  of  the  optical  antimer  of  the  first  tetra- 
hedron : 


the  projection  will  look  like  this 


the  arrows  indicating  the  difference  in  direction  of 
rotation.  Regarded  as  plane  formulae,  these  projec- 
tions are  of  course  identical;  considered  as  plane- 
pictures  of  the  solid  formulae,  they  are  different. 
Corresponding  projections  are  obtained  with  two  or 
more  asymmetric  carbon  atoms  : 


132        THE  SPIRIT  OF  ORGANIC  CHEMISTRY  ',. 

As  a  matter  of  economy  in  writing,  as  well  as  of 
convenience  in  reading,  it  has  become  customary  to 
represent  the  asymmetric  carbon  atoms  in  such 
formulae  by  the  intersection  of  the  valence  lines 
(just  as  in  aromatic  compounds  the  benzene  nucleus 
is  represented  by  a  hexagon)  : 


The  hexoses  contain  four  asymmetric  carbon  atoms: 
CH2OH-CH(OH)  -CH(OH)  -CH(OH)  -CH(OH)  - CHO  ; 

likewise  the  monobasic  acids  formed  from  them ;  and 
in  the  subsequent  development  the  formula  of  the 
sugar  will  be  used  for  the  acid  as  well.  It  will  be 
readily  seen  that  by  no  possibility  can  the  compounds 
become  optically  inactive  by  inner  compensation  as 
long  as  we  deal  with  the  sugars  themselves  and  their 
monobasic  acids ;  for  the  opposite  ends  of  the  mole- 
cule are  unlike :  CH2OH  on  the  one  hand,  CHO 
resp.  COOH  on  the  other.  Thus  even  a  perfectly 
symmetrical  arrangement  of  the  other  substituents 
cannot  bring  about  a  complete  symmetry  of  the 
molecule: 


THE  CONSTITUTION  OF  THE  SUGARS 
CHO 


133 


IT        C 

n     g 

TT         ( 

H         ^ 

OH         ^ 

The  case  is  different  with  the  dibasic  acids  and  with 
the  alcohols.  Here  the  ends  of  the  molecule  are 
identical,  and  therefore  when  the  remaining  sub- 
stituents  are  symmetrically  grouped: 


coon 


^     n 

n     C 

J     u 

n     v. 

^          TT 

r 

COOS 

the  compound  becomes  optically  inactive  by  intra- 
molecular compensation,  as  each  half  of  the  molecule 
is  the  mirrored  image  of  the  other. 

It  will  not  be  an  easy  task  for  the  reader  to  follow 
Fischer's  deductions  from  here  on;  continual  cross- 
references,  which  make  the  line  of  reasoning  appear 
confused,  are  necessary  in  order  to  bring  out  the 
genetic  connections.  But  with  a  little  patience,  and 
study  of  the  formulae,  the  difficulties  will  vanish. 
The  formulae  will  be  numbered  in  the  order  in  which 
taken  up,  and  reference  to  them  will  always  be  by 


134        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


this  number ;  for  convenience'  sake  they  are  given 
in  consecutive  order  on  Chart  II. 

Two   different   sugars,   glucose   and   gulose,   give 
saccharic  acid  ;  therefore  all  the  stereochemical  possi- 
bilities for  this  acid  are  contained  in  the  following 
formulae : 
l. 

COOH 


HO — - 


H 


#0-4- 

H— Q(-3r-OH 
-H 


H 


TT 


COOH 


2.                                  3. 

COOH                         COOH 

—  ^ 

$r-OH           H  —  - 

OH 

_  _ 

—H             HO— 

H 

2—  OH           HO—~- 

-  H 

^-OH              H  

—OH 

COOH 


COOH 


4. 

COOH 

5. 
COOH 

6. 

COOH 

H  

OH 

H  

OH 

HO  

H 

H  

-J—OH 

II  

OH 

HO-+- 

H 

H  

OH 

H  

OH 

HO— 

H 

H  

OH 

m  H 

H—— 

OH 

COOH 


COOH 


COOH 


Nos.  3  and  4  are  at  once  excluded,  as  they  represent 
inactive  compounds ;  and  the  following  considerations 
show  that  5  and  6  are  also  unsuitable.  Mannosac- 
charic  acid,  which  is  formed  by  oxidation  of  mannose, 
stands  in  the  same  relation  to  mannose  as  saccharic 
acid  does  to  glucose.  Now  we  have  seen  that  the 
two  sugars  differ  only  with  respect  to  the  asymmetry 
of  the  carbon  atom  next  to  the  aldehyde  group  (for 
they  give  the  same  osazone).  Therefore  if  saccharic 
acid  is  either  5  or  6,  mannosaccharic  acid  must  be 
either  4  or  3.  But  mannosaccharic  acid  is  not  in- 


THE  CONSTITUTION  OF  THE  SUGARS        135 


CHART  II 


1. 

2. 

3. 

4. 

CO  OH 

COOH 

COOH 

COOH 

HO  

H 

H  

OH 

H  

OH 

H  

OH 

H  

OH 

HO  

H 

HO  

H 

H  

OH 

HO  

H 

H  

OH 

HO  

H 

H  

OH 

HO  

jj 

H  

OH 

H  

OH 

H  

OH 

COOH 

1-  saccharic  acid 

COOH 

d-saccharic  acid 

COOH                  COOH 

mucic  acid   allomucic  acid  (?) 

5. 

6. 

7. 

8. 

COOH 

COOH 

CHO 

CHO 

H  

OH 

HO  

H 

H  

OH 

HO  

TT 

H  

—  -OH 

HO  

H 

HO— 

H 

HO  

—  H 

#-— 

OH 

HO  

H 

H  

OH 

H  

OH 

HO  

H 

H  

OH 

H  

OH 

HO  

H 

COOH 

1-talomucic  acid 

COOH 

d-talomucic  acid 

CH2OH 

d-glucose 

CH2OH 

d-gulose 

9. 

10. 

11. 

12. 

CHO 

CHO 

CHO 

CHO 

HO  

H 

HO  

H 

HO  

H 

H  

OH 

H  

OH 

H  

OH 

HO  

jj 

HO  

H 

H  

OH 

HO  

H 

H  

DH 

H  

OH 

CH2OH 

d-arabinose 

CH2OH 
d-xylose 

jr 

CH< 
d-mai 

OH 

>.OH 
inose 

HO  

CH, 

d-id 

H 

>.OH 
ose 

13. 

14. 

15. 

16. 

CHO 

CHO 

CHO 

CHO 

HO  

H 

H  

OH 

H  

OH 

HO  

H 

H  

OH 

H  

OH 

H  

OH 

H— 

OH 

HO  

H 

HO  

H 

HO  

H 

HO  

H 

HO  

H 

HO  

H 

H  

OH 

H  

OH 

CH2OH 
1-glucose 

CH2OH 
1-mannose 

CH2OH 
1-gulose 

CH*OH 
1-idose 

136        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


CHART  II  (continued) 


17. 
COOH 


18. 
COOH 


19. 

CHO 


CHO 


HO 

HO 


-OH 

-H 

-H 


COOH 

active  trioxy- 
glutaric  acid 


21. 

CHO 


-OH  H- 
-OH  HO- 
-OH  110- 


COOH 

inactive  trioxy- 
glutaric  acid 


-OH    HO 

-H         H 

-H         H 


H OH    tltf- — 


CH2OH 

d-galactonic 

acid 


CH 


-H 
-OH 
-OH 
-H 


OH 


1-galactonic 
acid 


22. 

CHO 


CHO 


TT 

H 

HO 


-OH 
-OH 
-H 


CHOH? 
CHa 
rhamnose 


HO 

H 

H- — 

HO 


-H 
-OH 
-OH 
-H 


H- 

H- 

II- 

HO- 


CHOH? 
CHS 

a-rhamnohexonic 
acid 


-OH 
-OH 
-OH 
-H 


CHOH? 
CH8 

/3-rliamnohexonic 
acid 


24. 

CHO 


25. 

CHO 


H 

H 

H 

HO 


-OH 
-OH 
-OH 
-H 


HO- 

HO- 

HO- 

H- 


-H 
-H 
-H 
-OH 


CH2OH 
1-talonic  acid 


CH2OH 
d-talonic  acid 


active,  therefore  does  not  possess  formula  4  or  3,  and 
consequently  saccharic  acid  cannot  be  5  or  6.  Thus 
only  1  and  2  remain  for  consideration.  These 
formulse  represent  merely  the  dextro  and  Isevo  modi- 
fication of  the  same  compound,  as  they  are  to  each 
other  as  object  and  mirrored  image.  Since  we  have 


THE  CONSTITUTION  OF  THE  SUGARS        137 


no  means  of  deciding  at  present  which  actual  order 
of  arrangement  corresponds  to  right  and  to  left, 
Fischer  arbitrarily  selected  2  for  d-saccharic  acid. 
This  arbitrary  choice,  however,  defines  once  for  all 
the  relative  arrangements  of  all  compounds  connected 
with  saccharic  acid. 

d-Saccharic  acid  thus  being  2,  and  being  further 
produced  by  the  oxidation  of  both  d-glucose  and 
d-gulose,  these  latter  must  be  : 


7. 
CHO 

H  

OH 

HO  

H 

H  

OH 

H  

OH 

CHO 


HO 

HO 

H 

HO 


-H 
-H 
-OH 
-H 


CH2OH  CH2OH 

Which  formula  belongs  to  each,  can  be  settled  by 
remembering  their  connections  with  the  pentoses. 
Glucose  is  derived  from  arabinose,  gulose  from  xylose 
(by  the  cyanhydrine  reaction).  If  the  asymmetric 
carbon  atom  resulting  from  the  addition  of  hydro- 
cyanic acid  to  these  sugars  be  removed  from  7  and  8, 
we  get : 


9. 

CHO 


HO 

H 

H 


-H 

-OH 

-OH 


HO 


10. 

CHO 

I 


H 

HO 


-OH 
-H 


CHZOH  CH2OH 

Only  one  of  these,  10,  can  yield  an  inactive  dicarbox- 
ylic  acid.  Now,  as  xylose  gives  inactive  trioxyglutaric 
acid,  it  possesses  this  formula  (accurately  speaking, 


138        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


it  belongs  not  to  ordinary  (Isevo)  xylose,  but  to 
its  optical  antimer).  9  is  then  the  formula  of 
d-arabinose.  From  these  facts  we  conclude  that 
d-glucose  is  7,  d-gulose  8. 

We  are  now  able  to  derive  the  formula  of  mannose. 
As  we  have  seen,  this  sugar  differs  from  glucose 
merely  by  the  asymmetry  of  the  carbon  atom  nearest 
the  aldehyde  group,  since  the  osazones  of  these  sugars 
are  identical.  By  reversing  the  arrangement  of  sub- 
stituents  on  this  carbon  atom,  we  get  : 

11. 
CHO 


HO 

HO 


-H 
-H 
-OH 
-OH 
CH2OH 

as  the  stereochemical  picture  of  d-mannose. 

Fischer  obtained  a  new  sugar  from  gulose  in  the 
same  manner  in  which  glucose  is  converted  into  man- 
nose,  viz.  by  oxidizing  it  to  gulonic  acid,  heating 
with  pyridine,  and  reducing  the  lactone  of  the  new 
acid  thus  obtained,  idonic  acid,  to  the  corresponding 
sugar,  idose.  The  formula  of  this  new  sugar  is  thus 
derived  from  that  of  gulose  (8),  by  the  process  just 
applied  to  mannose : 


12. 
CHO 


HO 

H 

HO 


•OH 
-H 
-OH 
-H 


CH2OH 


THE  CONSTITUTION  OF  THE  SUGARS        139 


Having  deduced  the  configurations  of  glucose  (7), 
mannose  (11),  gulose  (8),  and  idose  (12)  in  their 
dextro  modifications,  we  are  able  to  give  those  of 
their  optical  antimeres  offhand : 


13. 

CHO 

14. 

CHO 

15. 

CHO 

16. 

CHO 

HO  



H 

H  

OH 

H  

OH 

HO  



H 

H  



OH 

H  

OH 

H  

—OH 

H  



OH 

HO  



H 

HO  

H 

HO  

H 

HO  



H 

HO  



H 

HO  

H 

H  

OH 

II  



OH 

CH2OH 


CH2OH 


CH2OH 


CH2OH 


Eight  of  the  possible  sixteen  normal  hexa-aldoses 
are  therefore  determined  with  an  accuracy  dependent 
only  upon  the  legitimacy  of  the  fundamental  stereo- 
chemical  assumptions.  As  another  method  of  pro- 
cedure, starting  from  xylose,  leads  to  exactly  the 
same  configurations  as  those  just  given,  the  relia- 
bility of  these  deductions  of  Fischer's  is  greatly 
strengthened. 

The  dulcite  family,  including  galactose  and  mucic 
acid,  must  be  diagnosed  without  reference  to  the 
preceding  group  (the  mannite  family).  Mucic  acid 
is  optically  inactive,  and  therefore  possesses  one  of 
the  following  formulae  : 


3. 

CO  OH 


4. 

COOH 


H 

HO 

H 

H 


-OH 
-H 
-H 
-OH 


H- 
H- 
H- 
H- 


COOH 


-OH 
-OH 
-OH 
-OH 


COOH 


140        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


The  chain  of  reasoning  which  leads  to  3  is  rather 
complicated.     Rhamnose,  which  is  methyl-pentose  : 

CHs-CHOH-CHOH-CHOH-CHOH-CHO 
furnishes  an  active  trioxyglutaric  acid  upon  oxidation 
(one  carbon  atom  being  completely  split  off).  Now 
a-rhamnohexonic  acid,  which  is  obtained  from  rham- 
nose  by  the  cyanhydrine  reaction,  similarly  splits  off 
a  carbon  atom  when  oxidized  and  yields  mucic  acid, 
which  is  inactive.  The  asymmetric  carbon  atom 
introduced  by  addition  of  hydrocyanic  acid  must 
therefore  have  converted  an  active  system  of  three 
carbon  atoms  into  an  inactive  one  of  four.  Only  3 
meets  this  requirement ;  for  of  the  trioxyglutaric 
acids  which  might  be  obtained  from  the  two  formulae : 
17.  18. 

CO OH  CO OH 


H 

HO 

HO 


-OH 

-H 

-H 


H- 
H- 
H- 


•OH 
-OH 
OH 


CO OH  CO OH 

17  is  active,  and  18  inactive.     Mucic  acid  therefore 
possesses  configuration  3. 

D-  and  1-galactose  both  give  mucic  acid  upon  oxi- 
dation. They  therefore  have  the  following  optically 
antimeric  formulae : 

20. 

CHO 


19. 

CHO 

H  

OH 

HO  

H 

HO  

H 

\ 

H— 

OH 

HO- 
H- 
H- 

H0~ 


-H 
-OH 
-OH 
-H 


CH2OH 


CH,,OH 


THE  CONSTITUTION   OF  THE  SUGARS        141 

but  which  one  of  these  belongs  to  each,  cannot  be 
determined  directly,  since  mucic  acid  is  inactive  by 
intramolecular  compensation.  No  transitions  from 
the  mannite  to  the  dulcite  group  are  known,  or  the 
matter  would  be  very  much  simplified.  A  few  facts 
must  be  first  taken  into  account.  If  d-galactonic 
acid  is  heated  with  pyridine,  it  is  in  part  converted 
into  a  new  acid,  talonic  acid;  and  these  two  acids 
are,  of  course,  antimeric  with  respect  to  the  carbon 
atom  attached  to  the  carboxyl.  d-Talonic  acid  re- 
duces to  a  new  sugar,  d.-talose,  and,  on  oxidation, 
goes  over  into  a  difaasic  acid,  called  d-talomucic  acid. 
Mucic  and  talomucic  acids  are  therefore  also  anti- 
meric in  the  just-mentioned  sense.  Finally,  a-rham- 
nohexonic  acid,  which  we  have  seen  to  furnish  mucic 
acid  when  oxidized,  is  converted  into  its  antimer, 
/3-rhamnohexonic  acid,  by  heating  with  pyridine, 
and  this  yS-rhamnohexonic  acid  passes  over  into  a 
talomucic  acid  upon  further  oxidation  —  the  acid 
being  the  optical  (Isevo)  antimer  of  the  d-acid  ob- 
tained (indirectly)  from  galactonic  acid.  These 
facts  suffice  to  develop  the  configuration  of  d-  and 
1-galactose.  They  show  first  that  when  rhamnose 
(21,  Chart  II.)  and  its  derivatives  are  oxidized,  the 
methyl  group  is  split  off ;  for  the  «-  and  yS-rhamno- 
hexonic  acids  are  antimeric  with  reference  to  the 
first  carbon  atom  (counting  from  the  carboxyl); 
mucic  and  talomucic  acids  are  likewise  antimeric  in 
the  same  sense.  Now  when  the  rhamnohexonic  acids 
are  oxidized,  they  lose  a  carbon  atom ;  but  as  they 
yield  mucic  and  talomucic  acids  respectively,  con- 
taining the  same  antimeric  carbon  atom,  it  follows 
that  the  carbon  atom  split  off  does  not  come  from 


142        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


the  original  carboxyl  group.  Therefore  it  comes 
from  the  other  end  of  the  chain,  viz.  the  methyl 
group.  We  have  seen  that  rhamnose  gives  an  active 
trioxyglutaric  acid  when  oxidized,  to  which  formula 
17  was  ascribed  : 

17.         COOH 


H 

HO 

HO 


-OH 

-H 

-H 


COOH 


Following  out  the  genetic  relations  detailed  above, 
we  get  the  series  of  configurations  belonging  to  the 
group  : 


22. 


COOH 


23. 


COOH 


HO  

—H 

H— 

OH 

H  

OH 

H  

OH 

H  

OH 

H  

OH 

HO  

H 

HO  

H 

CH8.CHOH 

CH3  .  CHOH 

22  belongs  to  a-rhamnohexonic  acid,  because  this 
gives  mucic  acid  (3);  23  thus  remains  for  the  anti- 
meric  /3-acid.  Oxidation  of  23,  with  elimination  of 
the  methyl,  gives  for  1-talomucic  acid  formula  5  ; 
d-talomucic  acid  therefore  possesses  the  optically 
antimeric  configuration  6  : 


COOH 


6. 


COOH 


H  

OH 

HO  

H 

H  

OH 

HO  

jj 

H  

OH 

HO  

H 

HO  

H 

H— 

OH 

COOH 


COOH 


THE  CONSTITUTION  OF  THE  SUGARS        143 


By  reduction  of  these  acids,  d-  and  1-talonic  acids  are 
to  be  obtained ;  and  their  relations  to  the  rhamno- 
hexonic  acids  prove  that  the  lower  carboxyl  group 
is  reduced,  giving : 


24. 
COOH 


25. 

COOH 


H- 

H- 

H- 

HO- 


-OH 
-OH 
-OH 
-H 


HO 

HO 

HO 

H 


CH.2OH 


-H 
-H 
-H 
-OH 


COOH 


1-Talonic  acid  and  1-talose  (24)  are  still  unknown. 
d-Galactonic  and  d-talonic  (25)  acids  are  antimeric 
with  respect  to  a  single  carbon  atom ;  therefore 
d-galactonic  acid  possesses  formula  19,  and  1-galac- 

tonic  acid  20  : 

19.  20. 

COOH  COOH 


H 

HO 

HO 

H 


-OH 
-H 
-H 
-OH 


HO 

H- 

H- 
HO 


CH2OH 


-H 
—OH 
-OH 
-H 


CH2OH 


Eleven  isomeric  hexo-aldoses  thus  exist  to  verify 
the  predictions  of  stereochemical  theory ;  truly  an 
achievement  of  no  small  significance  for  the  legiti- 
macy of  such  speculations.  The  chapters  just  com- 
pleted form  by  far  the  most  important  part  of  the 
history  of  the  sugar  group ;  upon  them  all  future 
work  will  necessarily  be  founded.  Gaps  will  be  filled 
in,  new  compounds  added  to  the  already  lengthy  list ; 


144       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

valuable  data  will  be  made  available  for  physico- 
chemical  study  ;  and  the  chemistry  of  assimilation  is 
now  a  possibility.  This  last  direction  seems  the  most 
promising,  and  many  interesting  discoveries  have 
been  made  by  Fischer,  who  is  eagerly  following  up 
the  trail.  Thus,  he  has  found  that  only  sugars  con- 
taining 3,  6,  or  9  carbon  atoms  are  fermentable ; 
further,  that  a  certain  arrangement  of  the  hydroxyl 
groups  favors  fermentation ;  again,  that  yeast  attacks 
only  one  of  the  optically  antimeric  forms  of  a  given 
sugar ;  that  enzymes  are  selective  in  their  action  on 
sugar  derivatives ;  and  more  of  similar  importance 
and  interest.1 

In  order  to  simplify  the  nomenclature  and  the 
registration  of  compounds  of  the  sugar  group,  Fischer 
has  proposed  the  following  system  :  The  interna- 
tional nomenclature  is  to  be  employed  in  naming 
the  compound,  whereas  the  stereochemical  arrange- 
ment of  the  hydroxyl  groups  is  to  be  denoted  by  the 
4-  and  —  signs.  The  former  indicates  the  right, 
the  latter  the  left,  of  the  median  line,  Thus,  to  take 
two  examples,  glucose  would  be  called  : 

Hexose  H f-+    or    hexanpentolal  H f-H- 

while  d-saccharic  acid  is  catalogued  as  : 

Hexantetroldiacid  -\ f-+    or \-  — 

As  a  much  needed  complement  to  Fischer's  syn- 
thetic methods,  A.  Wohl2  has  given  us  a  reaction 
for  "building  down"  the  sugars,  i.e.  for  successively 

1  A  full  review  of  the  history  of  the  sugars  during  1896  is  given 
by  W.  E.  Stone,  Amer.  Chem.  J.  19,  608  (1897). 

2  Ber.  d.  chem.  Gesell.  26,  730  (1893). 


THE  CONSTITUTION   OF  THE  SUGARS        145 

removing  carbon  atoms  from  the  molecule.  Wohl 
availed  himself  of  the  fact  that  oximes  easily  lose 
water  to  form  nitriles : 

-CH  : NOH  =  -CN  +  H2O 

Glucosoxime  undergoes  this  reaction  when  heated 
with  acetic  anhydride  (the  hydroxyl  groups  being 
of  course  acetylated  at  the  same  time);  the  (acety- 
lated)  gluconitrile  thus  obtained  : 

/OH 
CH2OH-CHQH-CHOH-CHOH-CH< 

\CN 

loses  hydrocyanic  acid  on  treatment  with  ammoniacal 
silver  nitrate  solution,  to  pass  into  (acetyl)  pentose  : 

CH2OH-CHOH-CHOH-CHOH-CHO 

The  pentose  itself,  finally,  is  obtained  by  successive 
action  of  ammonia  and  dilute  acids  upon  the  acetyl 
body. 

In  this  manner  Wohl  obtained  d-arabinose  from 
d-glucose ;  this  new  sugar,  mixed  with  ordinary 
1-arabinose,  furnished  the  inactive,  pacemic,  arabi- 
nose.  The  method  promises  to  be  extremely  fruit- 
ful,1 and  has  very  recently  been  employed  by  Fischer.2 
Starting  with  rhamnose,  he  obtained  a  methyl-tetrose 
whose  configuration  must  be  : 

CHO 


TT 

HO- 

-OH 
-H 

CHOH  ? 
CH8 

1  Since  writing  the  above,  Wohl  has  applied  this  method  to 
galactose,  with  the  result  of  confirming  Fischer's  formula.     Ber. 
d.  chem.  Gesell  30,  3101  (1897). 

2  Ibid.  29,  1378  (1896). 


146       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Oxidation  of  this  leads  to  d-tartaric  acid ;  now,  as 
in  all  cases  heretofore  observed,  the  oxidation  of 
methyl-aldose  leads  to  elimination  of  the  methyl 
group,  a  similar  course  of  reaction  is  to  be  predicated 
here.  Therefore,  d-tartaric  acid  has  the  following 
configuration : 

COOH 


H- 
HO- 


-OH 
-H 


COOH 

Similarly  important  results  are  to  be  expected  shortly. 
There  remains  to  be  discussed  a  general  formula 
for  the  sugars  known  as  "  Tollens's  l  ethylene-oxide 
formula."  Owing  chiefly  to  the  fact  that  sugars 
do  not  give  the  fuchsine-sulfurous  acid  test  for  alde- 
hydes, as  well  as  that  sugars  differ  from  ordinary 
aldehydes  in  being  stable  in  the  air,  it  has  been 
suggested  by  Tollens,  and  contended  by  others,2 
that  the  aldoses  are  not  really  aldehydes,  but  inner 
anhydrides  of  hepta-oxy  compounds,  similar  to  ethy- 
lene  oxide  : 

CH2OH-CHOH-CH-CHOH-CHOH-CH-OH 


Such  compounds  would  readily  give  the  normal  reac- 
tions of  aldehydes  with  hydroxylamine  and  phenyl- 
hydrazine  ;  in  fact,  by  the  simple  assumption  of 
addition  of  water,  whenever  needed,  the  oxide  for- 
mula could  readily  pass  into  the  ordinary  one  : 

i  Ber.  d.  chem.  Gesell  16,  923  (1883). 

2Sorokin,  J.  prakt.  Chem.  37,  312  (1888);  Skraup,  Monats^h. 
10,  401  (1889). 


THE  CONSTITUTION   OF  THE  SUGARS        147 


/! 


CHOH 

I 

CHOH 
0(  | 
\  CHOH 
\  I     +  H20 
XCH 

CHOH 
CH2OH 


<H 
H 
CHOH 

I 
CHOH 

| 
CHOH 

I 
CHOH 

I 
CH2OH 


CHO 
I 
CHOH 

I 
CHOH 

| 
CHOH 

I 
CHOH 

I 
CH2OH 


H20 


Very  recent  facts  seem  to  make  this  view  plausible,1 
though  at  present  we  must  wait  for  something  more 
than  plausibility. 

A  subject  intimately  connected  with  this  formula 
of  Tollens  is  that  of  "multirotation."  Many  sugars 
have  a  different  specific  rotation  in  their  freshly  pre- 
pared solutions  than  when  the  solutions  have  been 
standing  for  some  time.  Usually  the  initial  rotation 
is  greater  than  the  final  ;  such  is  the  case  with  glu- 
cose, where  the  ratio  is  as  2  to  1,  or  with  fructose, 
whose  ratio  is  as  10  to  9,  or  with  xylose,  whose  origi- 
nal rotation  is  four  times  greater  than  its  final.  The 
reverse  phenomenon  has  also  been  observed  ;  maltose 
rotates  less  in  its  freshly  prepared  solutions  by  the 
ratio  of  8  to  9,  rhamnose  as  1  to  4.  These  curious 
facts  have  been  adduced  in  support  of  the  "  oxide  " 
formula  of  these  sugars,  as  well  as  in  refutation 
thereof.  It  is  readily  seen  that  on  the  assumption 
just  illustrated  (that  water  may  add  on  to  either 
the  aldehyde  or  the  ethylene-oxide  group)  we  can 
"  prove  "  both  formulse.  Fischer  has  suggested  that 
perhaps  the  aldehyde  structure  is  to  be  preferred  ; 

1  E.g.  the  existence  of  isomeric  glucoses.  Tanret,  Compt.  rend. 
120,  1060  (1894). 


148        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

for  the  sugar  could  dissolve  as  aldehyde,  and  grad- 
ually add  water  to  form  the  hepta-oxy-alcohol. 
Recent  investigations1  show,  however,  that  the 
molecular  weight  of  the  dissolved  sugar  in  its  initial 
and  final  conditions  of  rotation  is  one  and  the  same, 
which  fact  precludes  the  addition  hypothesis.  It 
has  therefore  been  proposed2  that  the  two  sugar 
solutions  differ  merely  in  containing  first  the  alde- 
hyde, and  then  the  oxide  structure  ;  the  two  forms 
must  necessarily  have  different  rotatory  powers, 
since  the  oxide  contains  a  new  asymmetric  carbon 
atom.  Certain  reactions,  as  yet  undeveloped,  appear 
to  indicate  that  the  oxide  is  the  final  structure;  such 
being  the  ready  conversion  of  glucose  into  fructose 
and  mannose  by  dilute  alkalies.3  These  reactions 
must  be  studied  farther  before  any  conclusions  can 
be  drawn  from  them.  The  real  cause  of  multi- 
rotation  is  still  a  mystery. 

The  chemistry  of  the  compound  sugars,  such  as 
cane  and  milk  sugars,  maltose,  etc.,  is  in  a  very  un- 
satisfactory condition.  It  is  well  known  that  these 
carbohydrates  are  easily  hydrolyzed  by  acids  into 
simpler  ones ;  cane  sugar  yields  glucose  and  fruc- 
tose, milk  sugar  gives  glucose  and  galactose,  maltose 
furnishes  two  molecules  of  glucose.  This  process  is 
known  as  inversion,  because  in  the  case  first  studied 
(cane  sugar)  the  direction  of  rotation  is  changed 
from  right  to  left.  This  reaction  of  the  compound 
sugars  has  given  them  the  name  "  polysaccharides," 

1  Trey,  Ztschr.  physik.  Chem.  18,  193  (1895);  22,  424  (1897). 

2  Lippmann,  Chemie  der  Zuckerarten  (1895);  Lobry  de  Bruyn, 
Ber.  d.  chem.  G-esell.  28,  3081  (1895). 

8  Lobry  de  Bruyn  and  van  Ekenstein,  I.e.  3078. 


THE  CONSTITUTION   OF  THE  SUGARS        149 

or  fo'oses,  tfn'oses,  etc.,  according  to  the  number  of 
simpler  sugars  they  form.  The  polysaccharides  are 
divided  into  two  distinct  groups :  the  members  of 
one  give  all  the  characteristic  reactions  with  phenyl 
hydrazine,  and  therefore  contain  the  aldehyde  or 
ketone  radical;  the  members  of  the  second  group 
are  indifferent  to  this  reagent,  and  thus  do  not  con- 
tain carbonyl.  The  first  group  includes  milk  sugar 
(lactobiose),  maltose  (maltobiose),  and  isomaltose1 
(isomaltobiose) ;  these  sugars  show  all  the  typical 
reactions  of  the  monosaccharides,  reducing  Fehling's 
solution,  adding  hydrocyanic  acid,  forming  mono- 
basic acids  when  oxidized,  etc.  The  second  group 
contains  cane  sugar  (saccharobiose),  besides  other 
not  well-known  substances  (trehalose,  etc.).  Vari- 
ous formulae  2  have  been  proposed  for  these  different 
sugars,  but  as  they  rest  more  upon  suppositions  than 
facts,  they  need  not  be  considered  here  for  the  present. 
Fischer  is  engaged  in  the  study  of  still  another 
branch  of  the  sugar  family :  the  so-called  glucosides. 
It  is  a  very  well-known  fact  that  many  substances 
occur  in  nature  combined  with  glucos'e,  in  rather  un- 
stable compounds,  e.g.  amygdaline,  salicine,  arbutine, 
digitaline,  etc.  The  glucosides  are  readily  hydro- 
lyzed,  by  acids,  alkalies,  or  enzymes ;  amygdaline 
gives  glucose,  benzaldehyde,  and  hydrocyanic  acid ; 
salicine  gives  glucose  and  saligenine  (o-oxybenzyl 
alcohol).  Occasionally  other  sugars  occur  in  this 

JA  "synthetic"  biose,  obtained  by  Fischer  [Ber.  d.  chem. 
Gesell.  23,  3687  (1890)].  It  is  formed  by  action  of  hydrochloric 
acid  on  glucose.  It  has  since  been  found  in  malt  and  artificial 
dextrine. 

2  Ber.  d.  chem.  Gesell  26,  2406  (1893). 


150        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

manner.  The  first  synthesis  of  a  glucoside  was 
effected  by  Michael,1  who  prepared  salicine  from 
salicylic  aldehyde,  by  treating  its  potassium  salt 
with  "  acetochlorhydrose '"  (obtained  by  action  of 
acetyl  chloride  on  glucose  ;  it  possesses  the  formula  : 
C6H7O  .  C1(O  .  C2H3O)4).  Many  others  have  been 
artificially  prepared  since  then,  without  any  particu- 
lar addition  to  our  knowledge  of  the  manner  in 
which  the  glucose  group  is  attached  to  the  rest  of 
the  molecule.  Fischer  is  attacking  this  problem  by 
the  investigation  of  the  simpler  compounds  of  the 
series.  This  study  has  not  led  to  very  tangible  re- 
sults, so  far,  though  it  has  been  rich  in  experimental 
facts.  All  the  sugars  seem  to  give  glucosides  with 
various  alcohols,2  in  the  presence  of  a  small  amount 3 
of  hydrochloric  acid.  The  reaction  proceeds  in  two 
steps ;  the  first  consists  in  the  formation  of  an  acetal  : 

CH2OH-CHOH-CHOH-CHOH-CHOH-CHO  +  2  CH3OH  = 

/OCH3 

CH2OH-CHOH-CHOH-CHOH-CHOH-CH<  +  H20 

X)CH8 

The  acetal  then  loses  one  molecule  of  alcohol,  and 
passes  into  the  glucoside.  The  nomenclature  of 
these  compounds  is  simple ;  their  names  are  formed 
by  taking  that  of  the  sugar  as  well  as  that  of  the 
alcohol  concerned;  e.g.  methyl  glucoside,  propyl 
mannoside,  butyl  galactoside.  It  has  been  much 
easier  to  name  these  substances  than  to  ascribe  a 
formula  to  them.  Two  isomeres 4  are  usually  formed; 

1  Amer.  Chem.  J.  1,  309  (1879). 

2  Ber.  d.  chem.  Gesett.  26,  2401  (1893). 
8  Ibid.  28,  1145  (1895). 

*  Ibid.  27,  2985  (1894). 


THE  CONSTITUTION  OF  THE  SUGARS        151 

this  is  easily  comprehensible,  since  by  the  process  a 
new  asymmetric  carbon  atom  has  been  produced. 
Two  formulse  have  been  proposed  : 

CH-OCHs  n  .CH-OCHg 

|  °<CH 

CH-OH  TT  CH-OH 

I  "•  CH-OH 

CH-OH  CH-OH 

CH2OH 

CH-OH 

CH2OH 

the  one  by  Fischer,  the  other  by  Franchimont  l  and 
by  Marchlewski.2  They  differ  with  regard  to  the 
carbon  atom  which  is  drawn  into  the  reaction  ;  in  all 
other  respects  they  agree  with  the  observed  isomer- 
ism  of  the  glucosides,  with  their  indifference  toward 
alkalies,  Fehling's  solution,  and  phenylhydrazine, 
and  their  extreme  sensitiveness  toward  acids  (which 
split  them  into  their  components).  Time  must 
decide  between  these  formulae.  Fischer  has  found 
that  the  sugars  readily  give  mercaptah  3  with  the 
thio-alcohols,  of  the  general  structure  : 


upon  the  investigation  of  which  he  bases  great  hopes. 
The  sugars  also  condense  with  one  and  with  two 
molecules  of  various  ketones,  but  the  constitution  of 
these  compounds  is  not  yet  known.  Here,  too,  the 
future  will  bring  us  needed  light. 

In  closing  this  sketch  of  the  sugar  group,  it  may 
not  be  amiss  to  refer  to  a  few  compounds  which  were 

1  Becueil  trav.  chim.  12,  312  (1893). 

2  Ber.  d.  chem.  Gesell.  26,  2928  (1893);  28,  1622  (1895). 
•Ibid.  27,  673  (1894). 


152       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

once  included  in  the  family,  but  have  since  been 
found  to  be  interlopers.  Chief  among  these  is 
inosite,  C6H12O6.  Maquenne1  has  shown  this  sub- 
stance to  be  hexaoxyhexahydrobenzene : 

H(OH) 
H(OH)/\H(OH)       ' 

H(OH)l      Jfi(OH) 
H(OH) 

Three  modifications  of  it  are  known,  as  well  as  many 
methyl-substitution  products  (pinite,  dambonite, 
quebrachite),  all  of  which  are  sugar-like  bodies. 
The  simplest  member  of  the  sugary  hydrated  ben- 
zenes was  recently  prepared  by  Baeyer,2  who  has 
named  it  chinite;  it  is  p-dioxyhexamethylene, 


H(OH) 


H(OH) 


and  resembles  inosite  in  its  general  properties. 

The  sugars  were  the  despair  of  the  earlier  chem- 
ists because  of  their  complex  reactions  and  uninvit- 
ing properties.  Scarcely  twelve  years  have  elapsed 
since  the  commencement  of  Kiliani's  and  Fischer's 
researches ;  this  brief  period  has  seen  the  establish- 
ment of  a  chapter  of  science  whose  completeness  is 
probably  unparalleled.  Many  gaps  remain  to  be 
filled ;  with  the  advance  of  our  knowledge  of  facts 

1  Ann.  chim.  phys.  Series  6,  12,  87  (1887). 
*Ann.  Chem.  (Liebig),  278,  88  (1894). 


THE  CONSTITUTION  OF  THE  SUGARS        153 

has  come  the  realization  of  deeper  problems  awaiting 
their  solution.  No  one  seems  to  feel  this  more 
keenly 1  than  the  man  who  has  led  us  thus  far  ;  but 
no  one  has  less  reason  to  despair  of  success  in  these 
more  difficult  fields  than  Emil  Fischer. 

i  Cf.  Ber.  d.  chem.  Gesett.  27,  3190  (1894). 


CHAPTER  VII 

THE  ISOMERISM  OF  MALEIC  AND  FUMARIC  ACIDS 

THE  problems  of  isomerism  have  always  possessed 
a  peculiar  interest  and  importance  in  the  history  of 
chemistry.  Aside  from  the  curiosity  such  questions 
invariably  arouse,  the  existence  of  isomeric  substances 
serves  as  a  touchstone  for  testing  the  worth  of  our 
theories.  When  Liebig,  in  the  dawn  of  organic 
chemistry,  discovered  that  cyan  uric  acid  was  abso- 
lutely identical  in  composition  with  cyanic  acid,  his 
first  impression  was  that  a  huge  mistake  had  been 
made  somewhere.  Chemical  theories  demanded  that 
identity  of  composition  should  amount  to  absolute 
identity.  When  the  fact  of  isomerism  became  clearly 
established,  it  was  manifestly  necessary  to  expand  the 
theoretical  horizon.  An  explanation  for  the  case 
cited  was  found  in  the  difference  of  molecular  weights 
possessed  by  the  two  compounds:  polymerism  at 
least  partially  accounted  for  isomerism.  When, 
subsequently,  isomerism  appeared  among  compounds 
of  equal  molecular  weight  and  comparatively  similar 
behavior,  the  next  step  in  the  evolution  of  chemical 
theory  was  the  establishment  of  our  modern  structural 
system.  In  this  way,  the  existence  of,  e.g.,  four  butyl 
alcohols  finds  its  satisfactory  justification.  And  when, 
finally,  the  limitations  of  structural  theory  failed  to 
account  for  two  isomeric  alpha-lactic  acids,  and  for 

154 


MALEIC  AND  FUMABIC  ACIDS  155 

four  dihydroxysuccinic  acids,  the  unravelling  of  the 
isomerism  involved  gave  us  the  theory  of  the  asym- 
metric carbon  atom  in  all  its  beauty  and  completeness. 

What  wonder,  then,  that  the  existence  of  two 
substances  certainly  not  polymeric,  containing  no 
asymmetric  carbon  atom,  and  apparently  structurally 
identical,  seemed  little  short  of  a  miracle.  Yet  the 
case  of  isomerism  presented  by  maleic  and  fumaric 
acids  could  hardly  be  considered  under  the  head  of 
any  other  known  phenomena.  And  as  might  have 
been  expected  by  historical  analogy,  the  solution  of 
this  problem  has  given  us  a  new  fundamental  concep- 
tion of  molecular  statics. 

When  malic  acid  is  subjected  to  dry  distillation,1 
the  chief  products  are  fumaric  acid  and  the  anhydride 
of  maleic  acid.  The  latter  substance  is  easily  con- 
verted into  maleic  acid  itself.  Both  acids  have  the 
same  composition,  C4H4O4,  and  are  diabasic ;  their 
formulae  may  therefore  be  partially  resolved  as 

follows : 

C2H2(COOH)2 

In  properties,  derivatives,  etc.,  there  is  the  widest 
possible  difference  between  these  two  substances. 
Fumaric  acid  does  not  melt,  but  volatilizes  above 
200°  ;  maleic  acid  melts  at  130°,  and  boils  at  160°,  at 
the  same  time  decomposing  into  its  anhydride  and 
water.  The  former  acid  is  difficultly  soluble  in 
water,  the  latter  easily.  Barium  fumarate  is  soluble, 
barium  maleate  is  insoluble.  The  dimethyl  ester  of 
the  former  is  a  solid,  of  the  latter  a  liquid.  Fumaric 
acid  crystallizes  in  irregular  needles,  maleic  acid  in 

1  Pelouze,  Ann.  Chem.  (Liebig),  11,  263  (1834). 


156        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

rhombic  prisms.  Evidently,  it  would  not  be  easy  to 
mistake  the  one  substance  for  the  other. 

But  the  most  curious  fact  regarding  the  relation 
of  the  two  acids  is  the  ease  with  which  they  are  con- 
verted into  each  other.  Thus,  all  attempts  to  convert 
fumaric  acid  into  its  anhydride,  whether  by  heating 
or  any  other  process,  yield  as  sole  product  the  anhy- 
dride of  maleic  acid.  On  the  other  hand,  if  maleic 
acid  be  maintained  at  a  temperature  slightly  above 
its  melting  point,  it  slowly  solidifies  as  fumaric  acid. 
A  similar  though  much  more  rapid  transition  is 
effected  by  concentrated  halhydric  acids,  hydriodic 
acid  acting  much  more  rapidly  than  hydrobromic  or 
hydrochloric  acids.  Maleic  ester  passes  into  fumaric 
ester  when  warmed  with  iodine. 

We  owe  most  of  our  systematic  knowledge  of  these 
transitions  to  Skraup,1  who  has  shown  that  these 
processes  do  not  take  place  quantitatively.  In  all 
cases,  other  substances  (chiefly  addition  products) 
are  formed  at  the  same  time.  Thus,  in  the  above 
reaction  with  hydrobromic  acid,  monobromsuccinic 
is  also  to  be  found  in  the  resulting  product.  Skraup 
also  discovered  that  substances  which  by  themselves 
have  no  effect  upon  maleic  acid,  partly  convert  it 
into  fumaric  acid  in  the  presence  of  atoms  upon  which 
they  can  react.  Thus,  hydrogen  sulphide  does  not 
act  upon  maleic  acid ;  but  if  copper  maleate  be  decom- 
posed by  the  gas,  a  considerable  quantity  of  fumaric 
acid  is  produced.  Evidently,  it  must  be  a  very 
subtle  and  unusual  variety  of  isomerism  which  unites 
these  curious  acids. 

i  Monatsh.  12,  107  (1891). 


MALE'iC  AND  FUMAE1C  ACIDS  157 

The  earliest  explanations  of  the  phenomenon,  natur- 
ally enough,  regarded  it  as  a  case  of  polymerism. 
Thus  Liebig,1  in  his  classic  treatise  on  the  constitu- 
tion of  organic  acids,  compares  this  case  to  that  of 
cyanic  and  cyanuric  acids.  Erlenmeyer2  remarked 
that  acids  might  be  regarded  as  oxy-aldehydes : 

,H  xOH 

-c=o  -d=o 

and  that  therefore  polymerization  is  to  be  expected 
among  acids,  aldehydes  being  peculiarly  prone  to 
this  form  of  condensation.  This  idea  was  finally 
disposed  of  by  Anschiitz.  Kekule  and  Anschiitz  had 
shown  that  when  maleic  acid3  is  oxidized  it  is  con- 
verted into  meso-tartaric  acid;  fumaric  acid,4  under 
the  same  conditions,  gives  racemic  acid.  Now 
racemic  acid,  being  a  mixture  of  dextro-  and  laevo- 
tartaric  acids,  was  regarded  as  a  bimolecular  sub- 
stance ;  and  its  relation  to  fumaric  acid  would  justify 
the  assumption  that  the  latter  is  also  bimolecular. 
Anschiitz5  showed  that  the  esters  of  both  racemic 
and  fumaric  acids  are  mono-molecular  ;  this  removed 
the  sole  basis  of  the  polymeric  hypothesis. 

The  question  received  considerable  impetus,  if  not 
marked  insight,  from  careful  experimental  investiga- 
tion by  Fittig.  Fittig  6  found  that  both  acids,  when 

1  Ann.  Chem.  (Liebig),  26,  168  (1838). 

2  Ber.  d.  chem.  Gesell  3,  342  (1870);  19,  1937  (1886).    See  also 
Markownikoff,  Ann.  Chem.  (Liebig),  182,  356  (1876). 

8  Ber.  d.  chem.  Gesell.  13,  2150  (1880). 
4  Ibid.  14,  713  (1881). 

6  Ann.  Chem.  (Liebig),  239, 161  (1887).     A  brief  account  of  the 
earlier  history  of  these  substances  is  given  in  this  article. 
«  Ibid.  188,  98  (1877). 


158        TEE  SPIRIT  OF  ORGANIC  CHEMISTRY 

treated  with  nascent  hydrogen,  gave  succinic  acid. 
This  proved  beyond  a  doubt  the  presence  of  the  fol- 
lowing chain  of  carbon  atoms  in  the  molecule  : 

I     I 
HOOC-C-C-COOH 

I      I 

leaving  the  two  hydrogen  atoms  still  to  be  accounted 
for.  A  second  result  of  this  investigation  was  the 
formation  of  two  different  dibrom-succinic  acids, 
according  to  which  of  the  two  substances  was  treated 
with  bromine.  Each  of  these  dibrom  products  was 
reduced  to  succinic  acid,  thus  proving  their  rela- 
tion to  this  latter  substance.1  Fittig's  third  result 
was  the  formation  of  one  and  the  same  mono-brom- 
succinic  acid  by  addition  of  hydrobromic  acid  to 
either  of  the  isomeres.  The  conclusion  which  Fittig 
draws  is  that  since  the  only  formulae  possible2  for 
two  dibrom-succinic  acids  are  : 

CHBr-COOH  CH2-COOH 

I.        |  and      |  II. 

CHBr-COOH  CBr2-COOH 

the  formulae  of  maleic  and  fumaric  acids  must  be  rep- 
resented by : 

CH-COOH  CH2-COOH 

I.        ||  and         |  II. 

CH-COOH  =C-COOH 

Of  these  two  structures  he  assigns  II.  to  maleic  acid. 

Fittig's   view  was   confirmed   by  Beilstein,3  who 

stated  that  the  dibrom-succinic  acid  obtained  from 

1  They  are  also  formed  when  succinic  acid  is  brominated  directly. 

2  It  must  be  remembered  that  this  statement  antedates  the  stereo- 
chemical  epoch. 

8  Beilstein  and  Wiegand,  Ber.  d.  chem.  Gesell  15,  1499  (1882). 


MALEIC  AND  FUMARIC  ACIDS  159 

maleic  acid,  when  treated  with  moist  silver  oxide, 
yielded  pyruvic  acid.  This  reaction  is  easily  ex- 
plained by  the  following  formulse  : 

CH2COOH          CH2COOH  CH3  CH3 

]  — M  — M  —*~\ 

CBr2COOH         C(OH)2COOH         C(OH)2COOH        CO-COOH 

But  a  reinvestigation  of  Beilstein's  results  by  V. 
Meyer  and  Demuth l  showed  the  former  to  have  been 
in  error  ;  no  pyruvic  acid  is  obtained  in  this  reaction. 
It  is  interesting  to  consider  the  condition  of  the 
problem  at  this  stage.  The  experimental  results  of 
Fit  tig,  V.  Meyer,  and  Demuth  left  not  a  shadow  of 
doubt  that  both  maleic  and  fumaric  acids  were  un- 
saturated  succinic  acids  of  the  structure : 

CH-COOH 

II 

CH-COOH 

Structural  chemistry,  it  would  appear,  had  exhausted 
its  resources ;  and  the  opinion  was  freely  expressed 
that  help  lay  only  in  the  direction  of  spatial  exten- 
sion  of  our  formulse.  But  how?  and  when?  The 
answer  came  almost  immediately  upon  the  question. 
It  was  another  illustration  of  the  inventive  energy 
of  necessity. 

But  while  stereochemical  speculations  were  gather- 
ing strength  and  material,  a  final  attempt  was  made 
to  save  the  day  for  structural  theories.  Anschiitz,2 
in  an  elaborate  experimental  and  critical  treatise,  ad- 
vanced a  new  formula  for  maleic  acid.  He  showed 

1  Ber.  d.  chem.  Gesell  21,  264  (1888).    The  substance  is  really 
brom-fumaric  acid. 

2  Ann.  Chem.  (Liebig),  239,  161  (1887). 


160        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

that  Fittig's  old  formula  for  this  substance  might  as 
well  have  been  assigned  to  f uinaric  acid ;  and  that, 
secondly,  it  could  belong  to  neither,  owing  to  the 
relations  existing  between  these  acids  and  racemic 
and  meso-tartaric  acids.  Anschiitz's  new  formula- 
tion is  as  follows: 

OH 


The  chief  argument  in  support  of  this  structure  of 
maleic  acid  appears  to  be  that  no  really  binding 
objection  to  it  can  be  stated  ;  but  it  assumes  an 
equivalent  for  the  carboxyl  groups  in  an  undoubted 
acid,  a  proposition  hardly  to  be  admitted  without 
debate.  However,  the  formula  never  took  on  formi- 
dable proportions ;  even  before  it  was  offered  to  the 
public,  the  long-expected,  generalized  solution  of  the 
difficulty  appeared. 

Wislicenus,1  in  a  brief  monograph,  summed  up 
the  situation  in  a  manner  which  has  since  received 
almost  universal  approval,  and  become  a  fundamental 
principle  of  organic  chemistry.  It  is  true,  there 
have  been  objections  and  criticisms,  which  we  shall 
in  part  consider  later;  but  there  is  little  doubt  of 
the  permanent  value  of  Wislicenus's  theory  of  "geo- 
metrical isomerism." 

Wislicenus  gives  us  a  development  of  the  earlier 
standpoint  of  stereochemistry.  It  will  be  remem- 
bered that  the  fundamental  conception  of  van  t'Hoff 
and  Le  Bel  lay  in  the  assumption  of  a  tetrahedral 

1  "Uber  die  raumliche  Anordnung  der  Atome,"  etc.  Trans. 
Saxon  Acad.  of  Sciences  (Math,  physical  section),  14  (1887). 


MALE'iC  AND  FUMAEIC  ACIDS  161 

form  of  the  carbon  atom,  or  at  least  of  a  tetrahedral 
spatial  distribution  of  the  four  valences  of  the  carbon 
atom.  This  assumption  led  to  the  asymmetry  of 
any  molecule  containing  a  carbon  atom  attached  to 
four  different  groups  of  atoms  (cf.  pp.  130  ff.).  This 
molecular  asymmetry  conditioned  the  existence  of 
two  spatially  similar  (or  enantiomorphic)  forms  of 
one  and  the  same  structural  formula.  And  it  will 
be  further  remembered  that  such  space  isomeres  dif- 
fered inappreciably  in  all  their  physical  and  chemical 
properties,1  save  one :  the  behavior  toward  polarized 
light.  It  is  plain  that  the  isomerism  of  maleic  and 
fumaric  acids  is  not  of  this  order;  and,  moreover, 
the  substances  do  not  contain  asymmetric  carbon 
atoms  at  all. 

Van  t'Hoff  2  had  summarized  his  views  into  three 
propositions : 

1.  The  radicals  of  a  compound  C-abcd  cannot  ex- 
change places  spontaneously. 

2.  Carbon  atoms  united  by  one  unit  of   affinity 
(bond  or  valence)  rotate  freely  around  their  common 
axis. 

3.  Freedom  of  rotation  is  inhibited  by  double  or 
triple  linkings. 

Van  t'Hoff  himself  had  drawn  certain  conclusions 
from  these  theorems,  but  except  in  so  far  as  they 
applied  to  optical  isomerism  they  had  escaped  gen- 

1  It  must  be  remembered,  however,  that  the  accumulation  of 
asymmetric  carbon  atoms  in  a  molecule  may  produce  extreme 
diversity  in  chemical  properties.     Witness  the  chemistry  of  the 
sugars. 

2  Stereochemistry,    translated    by  J.    E.    Marsh.     (Clarendon 
Press,  1891.) 


162       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

eral  notice.  In  particular,  he  had  clearly  enunciated 
the  formulae 1  now  accepted  for  our  two  acids ;  but 
the  extension  of  the  principle  to  a  large  number  of 
cases,  and  the  addition  of  three  other  theorems,  is 
due  to  Wislicenus. 

If  we  imagine  two  carbon  atoms  linked  by  a  single 
bond,  we  get  the  following  stereochemical  picture 
of  their  union ;  and  three  forms  are  possible,  accord- 
ing to  whether  the  rotation  of  substituents  in  the 
order  a-b-c-d  (where  d  represents  the  point  of  link- 
ing) is  the  same  in  both  atoms,  or  different : 


In  order  to  save  space,  it  has  become  customary  to 
abbreviate  these  configurations  thus  : 


When  the  carbon  atoms  are  doubly  linked,  the  fol- 
lowing appearance  is  presented  ;   and  here  two  forms 


1  La  chimie  dans  VEspace  (1877). 


MALEIC  AND  FUMARIC  ACIDS 


163 


are  possible,  according  to  whether  the  two  a  atoms 
are  adjacent  or  not : 


Here  again  it  is  convenient  to  save  space  by  attach- 
ing spatial  significance  to  our  plane  formulae  : 


a-C-b 

II 
a-C-b 


a-C-b 

II 
b-C-a 


Finally,  in  the  case  of  a  triple  bond  between  the  car- 
bon atoms,  we  have  but  one  possibility : 


and  stereo-isomerism  is  inconceivable  in  terms  of  our 
theory. 

On  this  basis,  van  t'Hoff  and  Wislicenus  assign 
the  following  formulae  to  maleic  and  fumaric  acids  : 


H-C-COOH 

II 

H-C-COOH 

Maleic  acid 


H-C-COOH 

HOOC-C-H 
Fumaric  acid 


This  choice  is  determined  by  the  fact  that  maleic 
acid  readily  forms   an  anhydride,  whereas  fumaric 


164       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 


acid  forms  none ;  it  is  quite  reasonable  to  attribute 
the  ease  of  reaction  in  the  one  case  to  proximity  of 
the  carboxyl  groups,  its  absence  in  the  other  to  the 
distance  between  them. 

In  order  to  determine  the  configuration  of  other 
substances  whose  isomerism  is  caused  by  a  double 
linking,  Wislicenus  has  set  up  three  subsidiary  theses ; 
these  have  the  further  function  of  explaining  the  be- 
havior of  such  isomeric  substances  under  varying 
conditions.  The  first  of  these  propositions  runs 
thus  :  When  a  compound  containing  a  triple  linking 
passes  by  addition  into  a  compound  with  a  double 
linking,  we  can  a  priori  determine  the  position  taken 
up  by  the  entering  constituents.  This  is  explained 
by  the  following  diagram : 


The  two  atoms  bb  take  up  the  m-position,  as  it  is 
called.1  This  form  of  reaction,  applied  in  the  prep- 
aration of  known  substances,  ought  to  settle,  once 
and  for  all,  the  spatial  relation  of  their  radicals. 
But  unfortunately,  fact  and  theory  do  not  yet  go 
hand  in  hand,  for  Michael2  has  adduced  a  large 

1  Because  they  are  on  the  same  side  of  the  plane  of  union.    The 
opposite  case  is  called  the  £mns-position. 

2  J.prakt.  Chem.  [2],  46,  402  (1892);  51,  517  (1895).    Michael's 
work  has  been  partly  nullified  by  later  investigations,  but  a  large 
number  of  contradictory  data  still  remain. 


MALEIC  AND  FUMAEIC  ACIDS  165 

number  of  instances  in  which  the  theory  is  sadly 
deficient. 

Wislicenus's  second  thesis  is  best  illustrated  by  an 
example.  To  account  for  the  conversion  of  maleic 
into  f  umaric  acid  by  means  of  a  small  quantity  of 
hydrobromic  acid,  we  have  the  following  series  of 
diagrams.  First,  the  maleic  acid  adds  on  a  molecule 
of  hydrobromic  acid : 

H 

H-C-COOH  H-C-COOH 

II  +HBr     =  | 

H-C-COOH  H-C-COOH 

Br 

forming  monobrom-succinic  acid.  The  two  halves 
of  the  molecule  now  rotate  on  their  common  axis 
into  this  position  : 

I    TT    I 

H 

|  I 

H-C-COOH            COOH-C-H  COOH-C-H 

I                   =  I                    =                   II 

H-C-COOH  H-C-COOH                       HC-COOH 

I  ,_!_,                                            +HBr 

Br  jBr! 

and  hydrobromic  acid  being  split  off,1  there  results 
fumaric  acid.  The  hydrobromic  acid  thus  acts  like 
a  ferment,  a  small  quantity  sufficing  to  convert 
an  unlimited  quantity  of  maleic  acid.  It  will  be 
admitted  that  this  explanation  possesses  much  ele- 
gance; but  it  does  not  accord  with  reality,  as 

1  If  this  rotation  is  repeated  with  the  aid  of  a  model,  it  will  be 
noted  that  a  different  hydrogen  atom  separates  than  the  one  first 
added. 


166       THE  SPIE1T  OF  ORGANIC  CHEMISTEY 

Anschiitz,1  Michael,2  and  Skraup3  have  shown.  If 
the  explanation  be  true,  then  monobrom-succinic  acid, 
the  supposed  intermediate  product  during  the  reac- 
tion, ought  to  lose  hydrobromic  acid  easily  and  form 
fumaric  acid.  As  a  matter  of  fact,  it  does  not  do  so 
except  under  conditions  by  no  means  comparable  to 
those  of  the  former  reaction. 

The  third  of  Wislicenus's  theorems  concerns  itself 
with  the  rotation  just  mentioned.     Given  a  molecule : 

b 

I 
a-C-c 

I 
e  -C-g 


there  must  be  certain  attractions  between  a,  b,  c,  e,  f, 
and  g  in  such  manner  that  one  position  of  the  two 
carbon  atoms  must  be  more  stable  than  the  others. 
If,  for  example,  a  possesses  a  very  strong  attraction 
for  f,  then  the  two  atoms  will  rotate  until  a  is  as  near 
as  possible  to  f ;  i.e.  until  a  and  f  are  superposed  : 

b 

I 
a-C-c 

I 
f-C-e 

ff 

This  more  stable  position  is  thus  the  "preferred" 
configuration  of  the  molecule,  and  while  the  position 

1  Ann.  Chem.  (Liebig),  254,  168  (1889).     See  also  Fittig,  ibid. 
259,  30  (1890). 

2  J.prakt.  Chem.  [2],  38,  21  (1888). 
s  Monatsh.  12,  107  (1891). 


MALEIC  AND  FUMAEIC  ACIDS  167 

may  be  disturbed  by  a  number  of  outside  agencies, 
the  tendency  to  return  to  the  preferred  location  must 
in  the  end  predominate.  It  is  for  this  reason  that  in 
the  above  case  of  transition  to  f  umaric  acid  the  mono- 
bromsuccinic  acid  molecule  rotated  as  shown ;  the 
latter  position  is  preferred. 

Here  again  there  are  unfortunate  contradictions 
to  disturb  and  perplex  us.  It  so  happens  that  the 
radicals  seem  to  be  inconstant  in  their  preferences ; 
and  while  Wislicenus  sets  up  one  table  of  attractive 
selection,  Baeyer  and  Bischoff,1  who  are  concerning 
themselves  with  similar  phenomena  in  other  fields, 
arrive  at  entirely  different  relations.  We  cannot 
within  the  limits  of  this  volume  discuss  situations  as 
yet  entirely  unsettled,  and  must  therefore  pass  over 
the  arguments  which  make  out  radical  A  to  be  more 
"positive"  or  more  "negative"  than  radical  B  — 
perhaps  the  remedy  will  come  when  the  misleading 
electrical  analogies2  are  discarded  in  favor  of  an 
unbiassed  study  of  facts.3 

Yet,  in  spite  of  the  failure  of  Wislicenus  to  com- 
pletely prove  his  standpoint,  the  conception  of  geo- 
metrical isomerism  has  been  extremely  valuable  to 
the  organic  chemist.  Even  though  many  details  are 
imperfect  and  contradictory,  we  have  been  enabled 
to  grasp  under  a  common  head  a  vast  number  of 
facts  for  whose  comprehension  we  had  no  guide. 
We  must  trust  to  time  to  remove  the  discrepancies 
or  evolve  the  successor  of  our  present  theory. 

As  to  the  critics  of  Wislicenus's  point  of  view,  they 

1  Cf.  the  discussion  in  R.  Meyer's  Jahrbuch,  1891,  133. 

2  Cf.  Michael's  "positive-negative"  hypothesis,  p.  77. 
8  Cf.  Lessen,  Ann  Chem.  (Liebig),  300,  30  (1898). 


168        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

must  bide  their  time  until  they  offer  us  something 
better.  In  so  far  as  they  merely  adduce  contradic- 
tions, we  must  wait  for  a  thorough  sifting  of  evi- 
dence and  of  theory.  Only  two  arguments  have  been 
advanced  against  the  theory  as  such.  Anschiitz1 
cannot  see  how  so  slight  a  difference  in  spatial  ar- 
rangement suffices  to  produce  such  difference  in  prop- 
erties.2 However,  the  world  is  full  of  wonders,  and 
this  seems  to  be  one  of  them.  After  all,  it  is  not  so 
strange  that  Kolbe  3  greeted  the  first  edition  of  van 
t'Hoff's  book  as  the  outburst  of  a  diseased  imagina- 
tion. Michael  argues  differently.  To  him  there  is 
an  essential  difference  between  double  and  single 
linking;  Wislicenus  —  van  t'Hoff  would  make  us 
believe  that  a  double  union  between  carbon  atoms  is 
simply  the  sum  of  two  single  unions.  Michael,  with 
perfect  consistence,  therefore  avoids  the  use  of  double 
bonds  in  his  formulae,  indicating  free  valences  by 
dots;  e.g.  his  formulse  for  maleic  (and  fumaric) 
acid: 

CH-COOH 

CH-COOH 

As  to  the  phenomenon  of  isomerism,  Michael  offers 
us  no  explanation ;  he  calls  it  allo-isomerism,  to  in- 
dicate its  difference  from  other  kinds  of  isomerism. 
Michael  further  objects  to  Wislicenus's  theory  because 
of  the  discrepancies  noted  above. 

The  majority  of  chemists  hold  with  Wislicenus 

1  Ann.  Chem.  (Liebig),  239,  165  (1887). 

2  Cf.  footnote,  p.  161. 

8  J.  prakt.  Chem.  [2],  15,  473  (1877).     This  passage  is  quoted 
in  the  edition  of  Van  t'Hoff's  work  noted  above. 


MALEIC  AND  FUMARIC  ACIDS  169 

rather  than  with  Michael.  Indeed,  we  have  no  other 
choice,  for  the  theory  of  geometric  isomerism  is  at 
least  tangible,  and  has  been  a  valuable  incentive  to 
further  investigation.  However,  it  would  appear 
that  Michael's  energetic  opposition  to  Wislicenus's 
views  might  be  mitigated  by  the  force  of  one  of 
Michael's  own  propositions.  It  is  undoubtedly  true 
that  the  mechanical  interpretation  given  for  the  trans- 
ition of  maleic  into  f umaric  acid  does  not  stand  the 
test  of  experiment ;  may  not  the  real  reason  be  the 
very  difference  between  double  and  single  Unkings  upon 
which  Michael  insists  ?  If  a  double  bond  is  not  sup- 
posed to  merely  open  on  one  side  to  leave  a  single 
one,  why  count  the  experimental  evidence  that  it 
does  not  do  so  against  the  fundamental  view  of  the 
structure  of  the  molecule  ? l  It  is  much  better  to 
admit  the  weight  of  evidence  in  favor  of  the  latter 
assumption,  and  admit  with  Michael  that  the  mechan- 
ism of  transition  is  as  yet  hidden  from  our  knowledge. 
There  is  no  cause  for  doubting  that  before  long  this 
mystery  also  will  be  disclosed  to  the  eager  eye  of  the 
investigator. 

1  Skraup,  Monatsh.  12,  107  (1891),  assumes  a  sort  of  internal 
resonance  as  the  cause  of  transition.  The  oscillations  produced  by 
certain  reactions  are  absorbed  by  the  maleic  acid  molecule,  which 
is  thereby  thrown  into  sympathetic  oscillation. 


CHAPTER  VIII 

THE  ISOMERISM  OF  THE  OXIMES 

THE  crucial  test  of  any  scientific  theory  is  its 
ability  to  rise  to  unforeseen  emergencies.  Witness 
the  steady  development  of  Dalton's  atomic  theory  — 
in  spite  of  the  unparalleled  expansion  of  all  branches 
of  chemistry  and  physics,  not  a  single  fact  is  to-day 
incompatible  with  the  theorems  of  1808  and  1811 
(the  date  of  Avogadro's  hypothesis).  The  doctrine 
of  the  linking  of  carbon  atoms  is  another  example  of 
this  innate  elasticity  of  a  really  fundamental  theory; 
modern  structural  chemistry  has  not  yet  outgrown 
the  foster-mother  of  its  infancy.  And  so  it  has  been 
with  the  van  t'Hoff-Le  Bel  conception  of  the  spatial 
distribution  of  carbon  valencies.  We  have  seen 
how  easily  this  theory  accounted  for  the  complicated 
phenomena  among  the  sugars;  we  have  learned  with 
what  success  it  has  been  applied  to  the  isomerism  of 
unsaturated  compounds.  It  was  not  to  be  expected 
that  a  hypothesis  primarily  intended  to  explain  the 
coexistence  of  carbon  compounds  would  be  capable 
of  direct  application  to  the  derivatives  of  other  ele- 
ments. Yet  recent  years  have  shown  such  to  be  the 
case,  and  thus  a  new  field  has  been  conquered  for 
stereochemistry. 

The  element  in  question  is  nitrogen;  the  deriva- 
tives in  point  are  the  oximes.  As  is  well  known, 

i70 


THE  ISOMERISM  OF  THE  OXIMES  171 

carbonyl  compounds  (aldehydes  and  ketones)  act 
upon  hydroxylamine  1  as  follows: 

Rv    ----------  Hx 

>C  i  O  +  H2  ,'  NOH  =  >C=NOH  +  H20 

(H)R/     '--  (H)R' 

The  resulting  compounds  are  called  oximes  (ald- 
oximes  or  Jcet  oximes).  They  possess  the  character 
both  of  bases  and  acids.  As  acids,  they  are  soluble 
in  alkalies  ;  as  bases,  they  form  rather  unstable  salts, 
such  as  the  following  : 

C6H6CH=NOH  .  HC1 

They  serve  for  the  important  purpose  of  separating 
and  identifying  their  mother-substances,  for  these 
properties  enable  us  to  handle  them  with  facility  in 
the  laboratory. 

Among  the  numerous  reactions  of  the  oximes,  but 
few  need  to  be  recounted  in  this  place.  In  the 
first'  place,  the  oximes  are  readily  broken  down  into 
their  constituents  by  the  action  of  concentrated 

acids  : 

H20  =  >CO  +  H2NOH 


The  action  of  acetic  anhydride  upon  them  is  pecul- 
iar ;  ketoximes  react  normally  to  form  acetates  : 

\C=NOH  +  (CH8CO)20  =      \C=NO  .  COCH8  +  CHgCOOH 

aldoximes,  on  the  other  hand,  lose  water  and  form 

nitrites*: 

!H 

R-C=NJOH  =  R-C=N 

1  V.  Meyer  and  various  pupils,  Ber.  d.  chem,  Gesell.  15,  1324, 
1525,  2778  (1882);  16,  170  (1883). 


172       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

This  latter  reaction  shows  a  close  connection  between 
aldoximes  on  the  one  hand,  and  acid  amides  on  the 
other;  in  fact,  these  isomeric  substances  differ  but 
slightly  in  structure  : 

R-CfeNOH  R-CO-NH2 

But  it  must  be  frankly  admitted  at  this  stage  that 
we  have  no  valid  proof  of  the  structure  just  assigned 
to  the  oximes.  At  the  time  of  their  discovery,  V. 
Meyer  and  Janny  deduced  it  from  the  fact  that  when 
treated  with  benzyl  chloride  in  alkaline  solution  ace- 
toxime  forms  an  O -ester  : 

(CH3)2C-NO .  C7H7 

But  the  history  of  acetoacetic  ester  has  taught  us 
how  little  faith  is  to  be  placed  in  reactions  of  this 
sort  (cf.  p.  73).  And  as  a  matter  of  fact,  we  shall 
soon  see  that  isomeric  N-esters  are  now  known  which 
have  been  prepared  in  a  precisely  similar  manner : 

/NC7H7 
R2CH<  | 
N0 

However,  except  for  a  certain  limited  period,  there 
has  been  no  disposition  upon  the  part  of  the  chemi- 
cal world  to  question  V.  Meyer's  original  structure 
of  the  oximes,  as  this  best  expresses  the  general  be- 
havior of  these  substances. 

As  has  been  mentioned  above,  the  oximes  are  im- 
portant because  they  serve  to  identify  aldehydes  and 
ketones  (substances  notoriously  difficult  to  manage 
when  not  perfectly  pure).  We  can  therefore  readily 


THE  ISOMEBISM  OF  THE  OXIMES  173 

understand  how  the  discovery  of  isomeric  oximes 
immediately  became  an  object  of  public  concern; 
for  the  diagnostic  value  of  these  derivatives  was 
impaired. 

The  substance  benzil  is  a  well-known  diketone 
which  is  very  easy  to  procure,  and  which  therefore 
is  frequently  employed  in  the  prosecution  of  charac- 
teristic ketone  reactions.  Thus,  V.  Meyer  had  pre- 
pared both  the  mono-  and  the  di-oxime  derived  from 
it,  early  in  the  course  of  his  oxime-research  : 

C6H5-C=:O  C6H5-C=O  C8H6-C=NOH 

I  I  I 

C6H6-C=O  C6H3^C=NOH  C6H6-C=NOH 


Now  if  these  formulae  actually  represent  the  struc- 
ture of  these  substances,  isomerism  is  hardly  to  be 
thought  of  ;  and  Meyer  was  considerably  astonished 
to  find  later  that  his  collaborator,  H.  Goldschmidt, 
had  run  across  a  second  modification  of  benzil- 
dioxime.1  The  press  of  other  duties  prevented  an 
immediate  examination  of  this  remarkable  phenome- 
non, and  it  was  not  until  1888  that  the  siege  was 
begun. 

In  the  meantime  another  instance  of  isomerism 
among  the  oximes  had  come  to  light.  In  1886 
Beckmann2  had  discovered  the  curious  molecular 
rearrangement  which  bears  his  name  (Beckmanri  '- 
sclie  Umlagerung).  When  oximes  are  treated  with 
dehydrating  agents  (phosphorus  pentachloride, 
acetyl  chloride,  fuming  sulphuric  acid,  etc.),  and 
then  poured  into  water,  they  are  rearranged  into 

1  Ber.  d.  chem.  Gesell.  16,  2176  (1883). 

2  I.e.  19,  988  (1886). 


174       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

acid  amides  ;  thus,  benzophenone  oxime  yields  ben- 
zanilide  : 

C6H6-C=(NOH)-C6H5    -  >-    C6H5-CO-NH-C6H6 

This  reaction  serves  to  emphasize  the  close  connec- 
tion between  oximes  and  amides.  Now,  in  applying 
this  reaction  to  the  oxime  of  benzaldehyde,  Beck- 
mann  found  that  instead  of  producing  the  corre- 
sponding acid  amide,  benzaldoxime  gave  birth  to  a 
new  isomere.1  Five  possible  structures  suggest 
themselves  for  these  substances  : 

OH  H  H 


I.  II.  III.  IV.  V. 

Of  these,  I  belongs  to  benzaldoxime  itself  ;  II  is  the 
structure  of  benzamide  ;  III  the  tautomeric  form  of 
benzamide  (cf.  p.  84);  V  is  the  formula  of  form- 
anilide  ;  IV  thus  remains  for  isobenzaldoxime,  as 
the  new  substance  was  called.  This  formula  is 
strengthened  by  the  peculiar  property  of  isobenzal- 
doxime  of  promptly  passing  back  into  ordinary 
benzaldoxime  ;  it  will  be  seen  that  the  simple  shift- 
ing of  a  hydrogen  atom  suffices  to  convert  one 
structure  into  the  other. 

But  while  the  existence  of  two  benzaldoximes 
offered  no  remarkable  difficulties  of  interpretation,  a 
severe  strain  was  put  upon  structural  theories  by  the 
two  dioximes  of  benzil.  It  is  true,  a  number  of 

1  The  isomerizing  agent  first  employed  in  this  case  was  dilute 
sulphuric  acid.  Ber.  d.  chem.  Gesell.  20,  2766  (1887).  We  now 
use  hydrochloric  acid  in  ether  solution. 


THE  ISOMEEIS1I  OF  THE  OXIMES  175 

"  blackboard  formulae "  can  be  constructed  to  face 
any  emergency ;  but  in  this  particular  instance  such 
a  method  of  escape  was  precluded  by  the  painstaking 
demonstration  given  by  V.  Meyer  and  Auwers l  of 
the  structure-identity  of  the  oximes  in  question.  As 
these  investigators  propose  a  stereochemical  solution 
of  the  problem,  it  was  clearly  their  duty  to  absolutely 
preclude  the  ordinary  structural  variety  of  isomerism. 
This  demonstration  was  based  upon  the  following 
facts :  In  the  first  place,  both  oximes  are  still 
derivatives  of  benzil,2  and  therefore  have  not  under- 
gone the  Beckmann  rearrangement.  Secondly,  both 
contain  two  hydrogen  atoms  directly  replaceable  by 
acetyl.  Thirdly,  both  yield  the  same  oxidation 
product :  3 

C6H6C=N-O 
I  I 

C6H5C=N-O 

And  finally,  the  oximes  possess  the  same  molecular 
weight,  and  are  therefore  not  polymeric.  In  passing, 
it  may  be  noted  that  Meyer  and  Auwers  here  for 
the  first  time  in  the  history  of  organic  chemistry 
employed  Raoult's  cryoscopic  methods  to  determine 
molecular  weights  —  a  method  brought  to  perfection 
by  Beckmann,  also  in  connection  with  the  oximes. 
We  may  thus  regard  it  as  reasonably  certain  that 
the  two  dioximes  possess  the  same  structure : 

C6H6-C=NOH 

! 

C6H6-C=NOH 

1  Ber.  d.  chem.  Gesell  21,  784,  3510  (1888). 

2  As  they  can  be  reconverted  into  benzil. 
8  Viz.  diphenylglyoxime  hyperoxide. 


1T6        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

and  that  the  cause  of  isomerism  is  to  be  sought  in 
the  spatial  arrangement  of  their  atoms.  But  the 
application  of  van  t'Hoff's  laws  (cf.  p.  161)  pre- 
sented serious  difficulties.  In  the  first  place,  the 
substances  contain  no  asymmetric  carbon  atom.  In 
the  second  place,  the  carbon  atoms  are  all  united  by 
single  linkings  ;  this  permits  of  freedom  of  rotation, 
and  therefore  excludes  isomerism.  The  argument 
followed  by  V.  Meyer  and  Auwers  is  that  since  no 
asymmetric  carbon  atoms  are  present,  and  since  the 
isomerism  is  an  unavoidable  fact,  the  theorem  that 
single  bonds  do  not  prevent  free  rotation  is  subject 
to  exceptions. 

In  particular,  the  oximes  of  benzil  are  such  an 
exception.  If  we  arrange  the  central  carbon  atoms 
of  these  substances  according  to  the  abbreviated 
formulae  of  Wislicenus  (p.  162),  we  get  the  follow- 
ing possible  spatial  configurations  (in  which  the 
symbol  n  —  n  represents  one  oximido  group): 


n 

n 

C6H5 

/\ 

l\ 

1 

7i-C-C6H6 

C6H6-C-w 

n-C-n 

1 

1 

^  —  ,  —  ' 

W_C-C6H6 

VI 

w-C-C6H6 
\l 

n-C-C6H6 

n 

n 

VI 

n 

Instead  of  merely  representing  phases  of  rotation, 
we  must  now  suppose  the  f ormulse  to  be  more  or  less 
stable  molecular  entities.  Similar  considerations 
apply  to  benzil  monoxime,  and  Meyer  and  Auwers 
thus  predict  the  existence  of  three  modifications  each 
of  mono-  and  di-oxime.  A  further  consequence  of 
this  new  theory  is  that  the  isomerism  of  the  two 


THE  ISOMEEISM  OF  THE  OXIMES  177 

benzaldoximes  cannot  be  traced  to  the  same  cause, 
since  they  contain  only  one  available  carbon  atom. 

Fortune  favored  the  new  theory  ;  for  Meyer  and 
Auwers  soon  found  a  second  monoxime  of  benzil.1 
Almost  immediately  afterwards,  the  third  modifica- 
tion of  benzil  dioxime2  was  discovered.  And  to 
clinch  matters,  benzophenone  3  yielded  but  one  oxime, 
as  predicted. 

Meanwhile,  the  investigation  of  isobenzaldoximej-^ 
was   producing   interesting    results   in   BeoEmann's 
hands.4    The  possibility  of  polymerism  was  excluded 
by  the  molecular  weight  of  the  new  substance.     The 
formula   of   a   tautomeric   benzamide  (imidobenzoic 

acid) : 

OH 


<v/il 
NH 


improbable  as  it  was,  lost  caste  altogether  by  the 
fact  that  isobenzaldoxime  did  not  show  the  behavior 
of  an  imido-ether,  and  that  but  one  benzyl  group 
can  be  introduced.  There  remained  only  the  struc- 
ture already  mentioned  : 


, 


This  solution  was  emphasized  by  the  results  of 
alkylation.  On  treatment  with  benzyl  chloride  in 
alkaline  solution,  ordinary  benzaldoxime  5  (usually 
distinguished  as  aZpAa-oxime)  gave  an  a-benzyl  ester, 


1  For  theoretical  reasons  this  was  called  7-benziloxime.     Ber.  d. 
chem.  Gesell.  22,  537  (1889). 

2  Lc.  22,  705  (1889).  8  I.e.  22,  537  (1889). 
4  I.e.  22,  429  (1889). 

6  I.e.  22,  513,  1531  (1889). 


178       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

a  liquid,  whereas  iso-(/3)benzaldoxime  yielded  a  solid 
/3-benzyl  ester.  A  closer  examination  of  these  esters 
showed  that  the  liquid  a-benzyl  derivative  obtained 
from  normal  benzaldoxime  contained  the  benzyl 
group  attached  to  oxygen,  and  that  it  therefore  pos- 
sessed the  following  structure  : 

C6H5CH=N  .  O  .  C7H7 

This  naturally  leads  to  the  ordinary  oxime  formula 
for  benzaldoxime.  The  solid  yS-benzyl  ester,  on  the 
other  hand,  contained  its  benzyl  group  attached  to 
nitrogen;  l  its  constitution  must  be  : 

N.C7H7 


and  that  of  isobenzaldoxime  itself  : 

/NH 
C6H5CH/| 

as  already  determined  by  other  reasons. 

If  further  proof  were  needed,  Beckmann's  synthe- 
ses 2  of  these  esters  clearly  and  completely  prove  the 
structures  assigned  to  them.  As  is  well  known, 
hydroxylamine  forms  two  series  of  substitution  prod- 
ucts —  one  containing  radicals  in  place  of  hydroxyl 
hydrogen,  the  other  in  place  of  amido  hydrogen.  In 

1  The  method  employed  for  such  determinations  depends  upon 
the  almost  invariable  fact  that  alkyl  groups  attached  to  nitrogen 
adhere  to  this  element  with  great  firmness.    Thus,  on  warming 
the    above    /3-benzyl  ester   with    hydriodic    acid,  benzyl-amine, 
CeHgCHaNHa,  results.     The  a-benzyl  ester,  under  the  same  cir- 
cumstances, gives  benzyl  alcohol,  CeH5CH2OH.      .  \2 

2  Ber.  d.  chem.  Gesell.  22,  1531  (1889). 


THE  ISOMEBISM  OF  THE  OXIMES  179 

the  case  of  the  benzylhydroxylamines,  for  example, 
we  have  the  following  substances  : 

a-benzylhydroxylamine    H^N.O.CyHj 
/3-benzylhydroxylamine    C7H7 .  NH .  OH 

These  alkylated  hydroxylamines  react  with  benzal- 
dehyde  to  form  the  two  benzyl  esters;  a-benzyl- 
hydroxylamine gives  the  liquid  a-ester  : 


C6H5CH=!0  +  H2!N.O.C7H7  =   C6H6CH=N.O.C7H7  +  H2O 

i 1 

/8-benzylhydroxylamine  yields  the  solid  yS-ester : 


H;N  .  C7H7  /N  .  C7H7 

C6H6CH=  0  +  I  !  =     C6H5CH<  I  +  H2O 

H!0  XO 


What  conclusion  more  natural  than  that  the  oximes 
themselves  are  similarly  constituted  ? 

The  Meyer- Auwers  theory  of  the  benzil  di oximes 
was  but  strengthened  by  this  demonstration  of  struc- 
ture-isomerism  on  the  part  of  the  benzaldoximes  ; 
and  its  authors  did  not  fail  to  emphasize  this  fact.1 
Aldoximes  and  ketoximes  would  thus  appear  to  be- 
long in  different  categories.  But  Beckmann's  further 
work  began  to  throw  doubt  upon  the  subject.  It 
will  be  remembered  that  Auwers  and  V.  Meyer 
argued  the  identity  of  the  benziloximes  from  the 
identity  of  their  oxidation  products.  By  the  same 
token,  the  benzaldoximes  ought  to  yield  different 
oxidation  products,  since  they  do  not  possess  identi- 
cal structure.  However,  Beckmann  found  that  both 
aldoximes  behave  alike  on  being  subjected  to  various 

1  Ser.  d.  chem.  Gesell.  22,  565  (1889). 


180       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

oxidizing  agents ; 1  and  he  is  led  to  the  conjecture 
that  aldoximes  and  ketoximes  are  similarly  con- 
stituted. 

Yet  if  this  suggestion  be  true,  then  the  two  mon- 
oximes  of  benzil  ought  to  behave  as  do  the  benzald- 
oximes.  According  to  Auwers  and  Dittrich,  however, 
this  is  not  the  case.2  On  benzylating  the  former, 
two  (m/^en-esters  are  produced.  Furthermore,  the 
results  of  synthesis  differ  from  Beckmann's.  a-ben- 
zylhydroxylamine  gives  a-O-benzyl-benzaldoxime  ;  /3- 
benzylhydroxylamine  does  not  give  the  7-0 -ester,  but 
a  third,  isomeric  N-ester  different  from  either  of  the 
known  ones.  It  is  clear  that  these  results  accord 
better  with  the  views  of  V.  Meyer  and  Auwers  than 
with  those  of  Beckmann. 

If  the  history  of  organic  chemistry  had  suddenly 
closed  at  about  the  middle  of  1889  the  chronicler 
would  have  summed  up  the  case  of  the  oximes  some- 
what in  this  fashion  :  Two  varieties  of  isomerism 
have  been  proven  to  exist  among  these  substances. 
Aldoximes  are  extant  in  two  structural  modifications, 
distinguished  by  the  presence  of  hydroxyl  and  imido 
groups.  Oximes  of  monoketones  do  not  form  iso- 
meres.  Mono-  and  di-oximes  of  diketones  exist  in 
three  stereomeric  forms  each.  The  best-known  case 
is  that  of  benzil,  of  which  three  di-  and  two  mon- 
oximes  have  been  prepared.  This  kind  of  isomerism 
demonstrates  that  carbon  atoms  do  not  rotate  freely 
around  their  common  axis. 

But  in  less  than  six  months  from  the  period  of  our 
fictitious  historian  each  and  all  of  these  statements 

1  Ber.  d.  chem.  Gesell.  22,  1588  (1889). 

2  I.e.  22,  1996  (1889). 


THE  ISOMERISM  OF  THE  OXIMES  181 

had  been  challenged  and  refuted.  In  the  first  place, 
H.  Goldschmidt  asserted  the  structural  identity  of 
all  oximes,  whether  derived  from  ketones  or  alde- 
hydes.1 His  argument  was  based  upon  the  reactions 
of  these  substances  with  phenyl  isocyanate.  This 
reagent  has  a  great  affinity  for  hydroxyl  and  imido 
groups,  with  which  it  forms  additive  compounds. 
Thus,  with  alcohol  it  forms  the  corresponding  phenyl- 
urethane  :  2 

C6H5  .  N=C=0  +  C2H6OH  =  C6H5  .  NH  .  CO  .  OC2H6 

With  imido-derivatives  it  produces  substituted  ureas  : 

C6H5  .  N=C=0  +  NH(C2H5)2  =  C6H5  .  NH  .  CO  .  N(C2H6)2 
e.g.  with  diethylamine  diethyl-phenylurea.  Gold- 
schmidt, to  whom  the  extended  use  of  this  substance 
as  a  hydroxyl  reagent  is  due,  found  that  the  oximes 
of  benzil  react  normally  to  yield  urethanes;  and 
these  urethanes  are  readily  decomposable  into  their 
constituents,  a  characteristic  of  this  class  of  sub- 
stances. This  was  to  be  expected,  at  all  events  ; 
but  the  behavior  of  isobenzaldoxime  was  perfectly 
similar  —  which  was  decidedly  unexpected.  Gold- 
schmidt did  not  hesitate  to  declare  his  conviction 
that  isobenzaldoxime  possessed  the  same  structure 
as  normal  benzaldoxime.  The  cause  of  isomerism 
is  left  undetermined.  "  Beckmann  has  proved  only 
that  the  benzyl  esters  are  structure-isomeric.  From 
this  we  can  draw  no  conclusions  as  to  the  oximes 

1  Ber.  d.  chem.  Gesell.  22,  3109  (1889). 

2  The  esters  of  carbamic  acid 


C0 

are  called  urethanes. 


182       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

themselves.  Whatever  the  real  cause  may  be,  we 
have  no  basis  for  assuming  different  reasons  for  the 
isomerism  in  the  two  groups."  In  support  of  this 
contention  Golds  chmidt  adduces  a  number  of  in- 
stances in  which  one  and  the  same  mother-substance 
gives  two  series  of  alkyl  derivatives.  (Of.  p.  72.) 

The  world  was  not  obliged  to  wait  long  for  an 
explanation  of  these  perplexing  phenomena.  Two 
months  later  Hantzsch  and  Werner,  in  a  purely 
critical  and  constructive  treatise,  solved  the  problem 
satisfactorily.1  If  we  compare  carbon  compounds 
with  those  of  nitrogen,  we  are  struck  by  a  certain 
formal  analogy  in  the  unsaturated  series.  Thus 
acetylene  bears  a  marked  resemblance  to  hydrocyanic 
acid ;  we  need  only  replace  one  CH  group  (which  is 
of  course  trivalent)  by  a  nitrogen  atom : 

CH  CH 

III  III 

CH  N 

Similarly,  substances  like  maleic  acid  resemble  the 
oximes :  CX2  CX2 

II  I! 

CX2  NX2 

II 
the  bivalent  group  CX2  is  replaced  by  the  equivalent 

NX.  The  novel  and  fundamental  idea  introduced 
by  Hantzsch  and  Werner  is  that  in  certain  instances, 
notably  the  oximes,  the  valences  of  nitrogen  do  not 
lie  in  a  plane.  Our  chief  reason  for  accepting  the 
doctrine  of  a  tetrahedral  carbon  atom  is  the  fact  that 
the  tetrahedron  offers  the  simplest  possible  explana- 
tion of  the  equal  spatial  distribution  of  the  four 

1  Ber.  d.  chem.  Gesell.  23,  11  (1890). 


THE  ISOMER1SM  OF  THE  OXINES 


183 


valences.  But  in  the  case  of  trivalent  nitrogen,  the 
simplest  assumption  is  that  the  valences  lie  in  a  plane 
with  the  centre  of  gravity  of  the  atom : 


Isomeric  compounds  such  as  Nabc  and  Nbca  would 
not  exist  if  this  assumption  is  correct.  Hantzsch 
and  Werner  ascribe  a  tetrahedral  shape  (not  neces- 
sarily regular)  to  the  nitrogen  atom,  and  thereby 
arrive  at  the  same  conclusions  concerning  the  oximes 
as  did  Wislicenus  about  maleic  and  fumaric  acids 
(p.  163).  The  following  diagrams  will  make  this 
clear.  If  we  regard  the  field  of  activity  of  a  nitro- 
gen atom  as  a  sphere,  then  on  the  basis  of  plane  dis- 
tribution the  three  valences  lie  in  the  equator.: 


The  Hantzsch-Werner  conception  locates  the  points 
of  affinity  in  a  circle  parallel  to  the  equator : 


184       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

On  applying  this  idea  to  the  case  of  the  oximes  we 
obtain,  e.g.,  for  the  benzaldoximes,  the  configurations  : 
C6H5-C-H  C6H5-C-H 


^OH  E 

N  N 

or  abbreviated  : 

C6H6-C-H  C6H6-C-H 

II  II 

N-OH  HO-N 

The  consequences  entailed  by  this  theory  differ 
materially  from  those  of  the  Meyer-Auwers  hypothe- 
sis. According  to  Hantzsch- Werner,  all  oximes  of 
the  general  formula 

X-C-Y 
II 
NOH 

exist  in  two  modifications.     Dioximes  are  to  be  ex- 
pected in  three  forms,  e.g.  the  benzil  dioximes : 

C6H6C  -  C  -  C6H6       C6H5C C  -  C6H5      C6H5C C  -  C6H5 

II   II  II      II  II    H 

HON  NOH         NOH  HON          NOH  NOH 

The  only  known  case  of  isomeric  monoximes  of 
the  above  general  type  at  the  time  were  the  benzal- 
doximes ;  and  as  structural  isomerism  was  by  no 
means  absolutely  precluded,  V.  Meyer  did  not  fail 
to  emphasize1  this  discrepancy  of  the  new  theory. 
It  was  perfectly  clear  that  a  well-authenticated  case 
of  this  sort  would  deal  a  death-blow  to  the  older 
theory.  The  irony  of  fate  willed  it  that  V.  Meyer 
and  Auwers  themselves  should  make  the  first  dis- 
covery. They  had  previously  found  but  one  oxime 

i  Ber.  d.  chem.  Gesell.  23,  597  (1890). 


THE  ISOMERISM  OF  THE  OXIMES  185 

of  benzophenone,  a  fact  in  accord  with  either  view ; 
but  now  it  appeared  that  the  oxime  of  p-chloroben- 
zophenone  exists  in  two  varieties.1  The  reign  of  the 
old  theory  is  over;  Hantzsch  and  Werner  have 
triumphed. 

The  history  of  the  oximes  is  thus  practically  closed. 
Meyer  and  Auwers2  offered  a  modification  of  the 
Hantzsch-Werner  hypothesis,  but  after  a  brief  and 
unimportant  discussion  have  accepted  the  rival  doc- 
trine reservedly.  Criticisms  from  other  sides  have 
appeared,  notably  Bischoff 3  and  Glaus 4 ;  but  these 
authors  have  added  nothing  to  our  knowledge  of 
the  subject,  and  we  may  pass  them  by  with  this 
reference. 

All  of  the  consequences  of  the  new  theory  have 
been  experimentally  verified,  and  it  has  even  been 
possible  to  determine  the  spatial  distribution  of  the 
atoms  in  these  compounds.  One  of  the  most  inter- 
esting cases  is  the  oxime  of  p-tolyl-phenyl-ketone : 6 

(p)  CH3 .  C6H4  .  CO  .  C6H6 

This  ketone  yields  two  oximes,  and  also  two  stereo- 
meric  O-benzyl  esters,  which  pass  into  each  other 
as  readily  as  do  the  oximes.  Similar  results  were 
obtained  by  Goldschmidt6  with  anisaldoxime  and 
m-nitrobenzaldoxime,  each  of  which  gives  structure- 

1  Per.  d.  chem.  Gesell.  23,  2403. 

2  I.e. 

»  l.c.  23,  1970. 

4  J.  prakt.  Chem.  (2),  44,  313  ;  45,  1,  377  (1891).    Cf.  Hantzsch, 
Ber.  d.  chem.  Gesell.  25,  1692  (1892). 

5  Ber.  d.  chem.  Gesell.  23,  2325,  2776  (1890). 

6  l.c.  23,  2163  (1890). 


186        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

identical,  stereomeric  O -methyl  esters.  The  stereo- 
isomerism  of  oxime  derivatives  is  the  best  possible 
proof  of  the  validity  of  a  spatial  hypothesis. 

A  word  as  to  the  nomenclature1  of  the  isomeric 
oximes.  Hantzsch  distinguishes  them  by  the  pre- 
fixes "  Syn  "  and  "  Anti "  ;  the  choice  is  determined 
by  the  following  rules:  The  prefix  indicates  the 
proximity  of  the  radical  attached  to  nitrogen  (OH  in 
this  case)  to  that  one  of  the  other  radicals  which 
follows  immediately  after  the  prefix.  E.g. : 

C6H5— C  -  C6H4  .  CH8  C6H6  -  C  -  C6H4  .  CH3 

HO-N  N-OH 

Syn-phenyltolylketoxime  Anti-phenyltolylketoxime 

or  or 

Anti-tolylphenylketoxime  Syn-tolylphenylketoxime 

If  one  of  the  other  radicals  is  capable  of  reacting 
with  the  group  attached  to  nitrogen,  —  as  e.g.  in  the 
aldoximes  hydroxyl  and  hydrogen  are  split  off  in 
the  shape  of  water,  —  the  prefix  is  so  chosen  that  the 
syllable  "syn  "  distinguishes  that  one  of  the  isomeres 
containing  said  reacting  groups  in  closer  proximity : 

C6H5-C-H  C6H5-C-H 

II  II 

N-OH  HO-N 

Benzsynaldoxime  Benzantialdoxime 

The  nomenclature  of  the  dioximes  is  similar.  In 
the  formulae  on  page  184,  the  one  with  hydroxyls 
adjacent  is  called  "  syn,"  the  one  with  hydroxyls  in 
juxtaposition  "anti,"  the  third  "amphi." 

The  configurations  of  individual  oximes  have  been 
ascertained  by  Hantzsch  according  to  the  following 

1  Ber.  d.  chem.  Gesell.  24,  3479  (1891). 


THE  ISOMER1SM   OF  THE  OX1MES  187 

principles.  Aldoximes,  as  already  mentioned,  easily 
pass  into  nitriles  by  loss  of  water.  That  one  of  the 
two  isomeres  which  does  so  most  easily  evidently 
contains  its  hydroxyl  adjacent  to  the  movable  hydro- 
gen atom  ;  ft-  or  isobenzaldoxime  is  more  readily 
dehydrated  than  the  ordinary  oxime,  therefore  it  is 
benzs?/naldoxime.  This  method  is  applicable  only 
to  aldoximes.  With  ketoximes,  Hantzsch  makes 
ingenious  use  of  the  Beckmann  reaction,  whereby 
oxinies  are  transformed  into  acid  amides.  In  the 
classical  case1  of  the  tolyphenylketoximes,  one  is 
converted  into  the  anilide  of  toluic  acid  ;  we  con- 
clude that  it  contains  the  phenyl  and  hydroxyl  radi- 
cals in  the  "  syn  "  position,  as  the  following  series 
will  make  clear  : 


CH8  .  C6H4-C—  OH    CH8  .  C6H4-CO 

-  >-  II  -  ^          I 

N-OH  y  N-C6H6  NH 

The  other  modification  is  converted  into  the  toluide 
of  benzoic  acid,  and  therefore  contains  hydroxyl  and 
tolyl  in  the  "  syn  "  position  : 


HO-C-C6H5  OC-C6H6 

HO-N  CH8.C6H4-N  CH8.C6H4-HN 

An  objection  which  has  been  made  against  the 
Hantzsch-  Werner  theory  is  that  all  oximes  do  not 
form  stereo-isomeres.  As  a  matter  of  fact,  until 
within  less  than  a  year  ago,2  no  stereomeric  oximes 
were  known  containing  only  one  aromatic  radical. 

1  Ber.  d.  chem.  Gesell  24,  13  (1891). 

2  Scharvin,  Ber.  d.  chem.  Gesell.  30,  2862  (1897). 


188       THE  SPIEIT  OF  ORGANIC  CHEMISTRY 

What  the  cause  of  this  curious  phenomenon  may  be, 
can  only  be  conjectured.  When  such  "mixed" 
oximes  undergo  the  Beckmann  reaction,  it  is  invari- 
ably the  aromatic  radical  which  changes  place  with 
the  hydroxyl.  We  may  conclude  that  these  sub- 
stances possess  the  configuration  which  this  reaction 
implies  ;  e.g.  acetophenone  oxime  : 

C6H5-C-CH8 

II 
HO-N 

and  that  for  unknown  reasons  the  other  modifica- 
tion is  too  unstable  for  isolation  by  the  laboratory 
methods  with  which  we  are  acquainted.  Similar 
circumstances  obtain  among  the  purely  aliphatic 
oximes  —  no  well-authenticated  cases  of  stereoisorner- 
ism  are  known.  A  possible  exception  may  lie  in  the 
discovery  by  Dunstan  and  Dymond1  of  two  different 
acetaldoximes ;  there  is  no  good  reason  for  doubting 
space-isomerism  in  this  case,  but  the  evidence  is  not 
as  clear  as  might  be  wished.2 

Hantzsch  has  made  strenuous  efforts  to  ascertain 
the  conditioning  factors  of  isomerism,  but  without 
much  substantial  success.  He  has  given  us  a  table 
of  radicals  in  their  order  of  preference  for  the 
hydroxyl  group  ("  syn  "-forming).3  But  the  con- 
ditions under  which  the  oximes  must  be  handled  in 


1  J.  Chem.  Soc.  1894,  206. 

2  On  the  other  hand,  v.  Miller  and  Plochl  have  come  to  the  con- 
clusion that  the  aliphatic  oximes  do  not  contain  an  asymmetric 
nitrogen  atom.     This  is  argued  from  the  fact  that  these  oximes 
add  hydrocyanic  acid,  whereas  aromatic  oximes  are  indifferent  to 
this  reagent.     Cf.  Ber.  d.  chem.  Gesell.  25,  2020  (1892). 

8  Ber.  d.  chem.  Gesell  25,  2164  (1892). 


THE  ISOMERISM  OF  THE  OXIMES  189 

the  laboratory  (in  the  form  of  salts,  esters,  etc.)  exer- 
cise a  marked  influence  upon  configuration,  so  that 
nothing  definite  can  be  predicted  of  their  behavior 
under  given  circumstances. 

The  Hantzsch-Werner  hypothesis  has  scored  its 
greatest  successes  in  the  oxime  group.  There  is 
nothing  in  the  general  formula : 

X-C-Y 

II 
N-Z 

which  should  make  exceptions  of  all  other  unsatu- 
rated  nitrogen  compounds.  But  strangely  enough, 
while  numerous  attempts  have  been  made  to  include 
other  classes  of  substances  under  the  stereochemistry 
of  nitrogen,  none  of  these  has  advanced  beyond  a 
purely  tentative  stage.  Various  isomeric  hydrazones,1 
aniles2  (condensation  products  of  aldehydes  with 
aniline  and  other  aromatic  bases),  osazones,3  etc.,4 
have  appeared  on  the  scene,  but  it  has  not  been  easy 
to  incorporate  them  into  the  stereochemical  fold 
with  perfect  consistence.  As  this  is  a  branch  of  the 
subject  still  in  its  infancy,  it  will  be  best  here  to 
avoid  the  presentation  of  uncertain  facts  ;  references 
to  the  literature  in  question  must  suffice. 

One  branch  of  the  stereochemistry  of  nitrogen, 
however,  has  attained  to  sufficient  proportions  to 
warrant  separate  mention.  During  the  last  few 

1  Per.  d.  chem.   Gesell.  26,  18  (1893) ;   Compt.  rend.  116,  718 
(1893);  Amer.  Chem.  J.  16,  102  (1895). 

2  Monatash.  14,  279  (1893);  Ber.  d.  chem.  Gesell.  27, 1297  (1894). 
8  Gazz.  chim.  ital  26,  444  (1896). 

4  Ber.  d.  chem.  Gesell.  25,  3098  (1892);  26,  926,  3064  (1893). 


190        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

years,  a  most  curious  and  perplexing  isomerism  has 
come  to  light  among  the  diazo  compounds.  Hantzsch 
has  attempted  to  explain  these  phenomena  on  a  spatial 
basis ;  with  what  degree  of  success  will  be  seen  from 
the  detailed  account  given  in  the  chapter  on  the  con- 
stitution of  diazo  compounds  (pp.  215  ff.). 

It  is  a  far  cry  from  the  atomic  theory  of  Dalton 
to  the  conceptions  of  van  t'Hoff-Le  Bel  and  Hantzsch- 
Werner.  Well  might  chemistry  rest  upon  her  laurels 
and  point  with  pride  to  the  achievements  of  the  ebb- 
ing century.  But  per  aspera  ad  astro,  has  been  the 
watchword  of  the  organic  chemist,  and  we  may  feel 
certain  that  each  new  generation  will  have  its  own 
triumphs  and  its  own  difficulties. 


CHAPTER  IX 

THE  CONSTITUTION  OF  THE  DIAZO  COMPOUNDS 

IN  the  earlier  chapters,  we  have  seen  how  steadily 
the  chemistry  of  carbon  has  progressed ;  how,  step 
by  step,  the  doctrine  of  linked  atoms  has  unravelled 
the  structure  of  complicated  substances ;  has  ex- 
panded into  the  theory  of  ring-compounds ;  and, 
finally,  was  even  capable  of  extension  in  a  direction 
hardly  dreamed  of  by  its  founders  —  witness  the 
marvellous  development  of  stereochemistry  during 
the  last  fifteen  years.  The  dogma  of  the  quadrival- 
ence  of  carbon  has  been  able  to  withstand  all 
attacks  made  upon  it ;  all  its  logical  consequences 
have  been  experimentally  verified.  It  matters  not 
that  we  are  still  unable  accurately  to  account  for 
the  full  number  of  valences  in  benzene,  nor  that 
the  existence  of  a  number  of  substances  containing 
bivalent  carbon  has  been  demonstrated,  —  to  what 
new  heights  these  divergences  may  lead  we  do  not 
know  ;  but  one  fact  is  plain  :  the  theory  of  valence, 
and  the  additional  theory  of  a  comparatively  con- 
stant valence,  has  fully  justified  its  existence.  What 
wonder,  then,  that  these  theories  have  attempted  to 
sway  the  destinies  of  other  elements,  and  claimed 
to  be  the  one  true  faith. 

Indeed,  at  present  chemists  have  no  other  hope 
of  salvation.  Without  the  valence  theory,  our  specu- 

191 


192       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

lations  drift  hopelessly  from  one  quagmire  to  another, 
devoid  of  any  certain  basis.  And  yet,  at  this  very 
moment,  the  chemist  is  tunnelling  beneath  the  rock 
which  alone  sustains  him  —  tunnelling  among  the 
mysteries  of  the  compounds  of  nitrogen.  During 
the  last  ten  years,  this  element  has  been  engrossing 
the  attention  of  investigators  in  a  constantly  in- 
creasing degree,  though  each  succeeding  year  but 
serves  to  deepen  the  mystery.  It  has  long  been 
generally  understood  that,  in  its  compounds,  nitro- 
gen is  either  trivalent  or  pentavalent ;  but  this  tacit 
assumption  begins  to  show  signs  of  distress,  and  the 
very  idea  of  valence  itself  is  threatened.1  The  battle 
rages  all  along  the  line  of  nitrogen  chemistry,  but 
chiefly  among  the  diazo  compounds,  the  first  to  draw 
attention  to  the  vagaries  of  the  nitrogen  atom. 

The  diazo  compounds  were  discovered  in  1858 
by  Peter  Griess.2  The  first  detailed  description  of 
them  was  published  two  years  later,3  and  the  fol- 
lowing accounts  were  scattered  throughout  the  next 
six  years ;  though  occasional  notes  from  Griess's 
pen  occur  for  twenty  years  more.  It  will  be  best 
in  this  place  to  recount  Griess's  achievements  de- 
scriptively rather  than  historically,  even  though 
thereby  we  lose  sight  of  the  wonderful  beauty  of 
his  experimental  investigations.  It  is  difficult  to 
convey  the  attitude  of  contemporary  workers  toward 
these  masterly  researches.  Not  alone  did  the  abso- 
lute novelty  of  the  substances  described  by  Griess 
arouse  amazement,  but  the  consummate  skill,  the 

i  Cf.  Briihl,  Ber.  d.  chem.  Gesell  31,  1350  (1898). 
«4ww.  Chem.  (Liebig),  106,  123  (1858). 
8Z.c.  113,  201  (1860). 


THE  DIAZO   COMPOUNDS  193 

mastery  of  laboratory  technique,  the  versatility  dis- 
played during  the  progress  of  the  investigation, 
called  forth  the  enthusiastic  admiration  of  every 
competent  critic,  —  a  homage  which  the  recent  de- 
velopments in  the  field  of  diazo  chemistry  have 
served  but  amply  to  confirm. 

As  is  well  known,  when  nitrous  acid  acts  upon 
ami'$o  compounds,  the  amr^O  group  is  replaced  by 
hydroxyl : 

K-NH2  +  HN02  =  K-OH  +  N2  +  H20 

This  reaction  was  discovered  by  Piria,1  who  by  this 
means  converted  asparagine  into  malic  acid.  Certain 
observations  made  in  Kolbe's  laboratory  led  that  brill- 
iant chemist  to  suspect  the  existence  of  an  inter- 
mediate compound  in  Piria's  reaction  when  applied 
to  aromatic  amines,  and,  at  his  suggestion,  Griess 
undertook  the  investigation.  Griess  isolated  his  first 
diazo  compound,  as  he  decided  to  call  the  new  class 
of  substances,  by  working  with  alcohol  as  a  solvent ; 
subsequently  he  was  able  to  dispense  with  this  ex- 
perimental aid,  for  the  early  experiences  with  his 
new  substances  taught  him  how  they  might  be  ob- 
tained under  simpler  circumstances.  In  short,  Griess 
found  that  whenever  nitrous  acid  acts  upon  aromatic 
amines,  no  matter  what  the  solvent  nor  how  the 
nitrous  acid  is  introduced,  a  diazo  compound  is 
formed,  provided  the  temperature  be  kept  below 
the  decomposition-point  of  the  new  substance.  *  His 
first  and  favorite  means  of  employing  nitrous  acid 
in  these  reactions  was  to  pass  the  gas,  commonly 
known  as  nitrogen  trioxide,  into  the  given  solutions  ; 

.  Chem.  (Liebig),  68,  348  (1846). 


194       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

but  any  soluble  nitrite  could  be  substituted,  the  acid 
being  liberated  by  a  stronger  mineral  acid  ;  at  times, 
Griess  even  used  ethyl  and  amyl  nitrites  for  this 
purpose.  If  the  solid  reaction-product  was  re- 
quired, concentrated  solutions  were  taken,  or  by 
addition  of  suitable  solvents  it  was  precipitated  in 
crystalline  form  ; l  but  fortunately,  for  most  pur- 
poses, a  dilute  aqueous  solution  is  sufficient  or  even 
preferable. 

The  diazo  compounds  are  characterized  by  extreme 
instability  and  by  the  variety  of  their  reactions.  In 
the  solid  state  most  of  them  are  explosive,  diazoben- 
zene  nitrate  being  the  most  dangerous  of  all.  In 
solution  they  quickly  decompose,  giving  off  nitrogen, 
and  forming  complicated  products  of  unknown  com- 
position. Under  definite  circumstances,  however, 
the  decomposition  may  be  made  to  take  definite 
directions. 

The  analysis  of  these  substances  proved  a  matter 
of  no  small  difficulty.  The  first  few  diazo  compounds 
happened  to  be  comparatively  stable,  so  that  their 
composition  could  be  determined  fairly  safely ;  with 
the  information  thus  gained,  Griess  was  able  to  make 
skilful  use  of  a  decomposition  reaction  to  determine 
the  composition  of  the  other  members  of  the  family. 
Thus,  when  diazobenzene  nitrate  is  warmed  with 
dilute  sulphuric  acid,  it  breaks  down  into  nitric  acid, 
phenol,  and  nitrogen : 

C6H5N2N03  +  H20  =  HN03  +  N2  +  C6H5OH 

1  A  better  method  has  been  given  by  Knoevenagel  (Ber.  d.  chem. 
Gesell.  23,  2994).  It  consists  in  employing  alcohol  as  a  solvent, 
and  amyl  nitrite  as  the  diazo  tizer. 


THE  DIAZO  COMPOUNDS  195 

By  determining  the  amount  of  acid  set  free,  and 
above  all  the  quantity  of  nitrogen  given  off,  it  is 
possible  to  accurately  gauge  the  composition  of  the 
substance.  The  estimation  of  diazo  nitrogen  thus 
becomes  one  of  the  most  important  analytical  meth- 
ods in  this  branch  of  chemistry. 

The  reactions  of  the  diazo  compounds  are  ex- 
tremely varied.  As  might  be  expected  of  a  sub- 
stance containing  so  much  nitrogen,  the  diazo 
complex  is  strongly  base-forming.  Griess  prepared 
numberless  salts  not  only  of  diazobenzene  itself,  but 
of  a  great  quantity  of  substituted  diazobenzenes, 
diazotoluenes,  etc.1  Examples  are  diazobenzene 
nitrate,  chloride,  sulphate  : 

C6H5N2.N03        C6H5N2.C1        ( 
diazo-p-toluene  nitrate  : 


N2.N08(p) 
p-brom-diazobenzene  bromide  : 

.  Br 
Br(p) 

As  a  rule,  in  preparing  a  diazo  compound  such  a  salt 
is  obtained  first,  which  then  serves  as  the  starting- 
point  for  the  numerous  reactions  which  characterize 
this  class  of  substances.  The  general  feature  of 
most  of  these  reactions  is  the  elimination  of  nitrogen 
from  the  molecule.  Thus,  all  of  the  salts  mentioned 
above,  when  boiled  with  a  dilute  acid  (preferably 

1  Ann.  Chem.  (Liebig),  137,  39  (1866). 


196       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

dilute  sulphuric  acid),  lose  all  their  diazo  nitrogen, 
and  form  phenols  : 

C6H5N2  .  Cl  +  H20  =  C6H5OH  +  N2  +  HC1 

This  simply  carries  to  its  conclusion  Piria's  reaction, 
whereby  the  action  of  nitrous  acid  upon  amines  pro- 
duces alcohols.  If  in  the  above  decomposition  ^dilute 
acids  be  replaced  by  concentrated  ones,  the  reaction 
takes  an  entirely  different  course.  Concentrated 
hydrochloric  acid  yields  chlorbenzene  : 

C6H5N2  .  N03  +  HC1  =  C6H5C1  +  N2  +  HNO8 
hydrobromic  and  hydriodic  acids  act  similarly  : 


CHN     Cl  +  =     65  2  +  HCl 

f  \  HI     =  C6H5I  +  N2  +  HC1 

By  this  means  we  are  able  to  replace  any  amido- 
group  in  an  aromatic  molecule  by  one  of  the 
halogens  ;  and  since  nitro-  (and  therefore  amido-) 
groups  are  much  more  easily  introduced  into  the 
benzene  ring  than  chlorine  or  bromine,  these  diazo 
reactions  of  Griess  are  valuable  laboratory  adjuncts.1 
But  the  decomposition  of  diazo  compounds  by 
means  of  acids  does  not  exhaust  the  capabilities  of 
this  Protean  class  of  substances.  If  they  are  boiled 
with  alcohol  (preferably  in  the  presence  of  an  alkali), 
the  diazo  complex  is  eliminated  entirely  and  replaced 

1  The  value  of  this  series  of  reactions  has  been  greatly  aug- 
mented by  a  discovery  of  Sandmeyer  (Ber.  d.  chem.  Gfesell.  17, 
1633  (1884)).  In  the  presence  of  cuprous  salts,  the  replacement 
of  the  diazo  group  takes  place  much  more  readily  ;  we  may  even 
introduce  the  cyanogen  group  in  this  way,  and  can  thus  build  up 
aromatic  acids.  For  details  of  this  method,  and  of  a  modification 
by  Gattermann,  consult  any  larger  text-book  or  laboratory  manual. 


THE  DIAZO  COMPOUNDS  197 

by  hydrogen  ; 1  the  alcohol  becomes  oxidized  to  alde- 
hyde during  this  process : 

C6H5N2  ,  N08  +  C2H60  =  C6H6  +  N2  +  HN08  +  C2H40 

A  by-product   of  the   reaction  is  the  hydrocarbon 

diphenyl,   evidently  formed  by  the   union   of   two 

nascent  phenyl  groups : 

2  C6H5N2  .  N03  +  C2H60  =   (C6H5)2  +  2  N2  +  2  HN03  +  C2H4O 

Even  this  elimination  reaction  has  its  value ;  e.g.  in 
the  preparation  of  meta-toluidine.2  The  direct  nitra- 
tion of  toluene  yields  a  mixture  of  the  ortho-  and 
para-nitrotoluenes,  which  upon  reduction  of  course 
give  the  corresponding  toluidines.  The  meta-deriva- 
tive  cannot  be  prepared  in  this  way.  But  if  we 
nitrate  para-toluidine,  the  entering  nitro  group  takes 
up  the  meta-position  with  reference  to  the  methyl 
group  : 

CH3  CH8  CH8 


NH2  NH2 

The  amido  group  is  then  eliminated  as  just  described, 
and  there  remains  meta-nitro-toluene. 

A  further  curious  reaction  is  given  by  diazobenzene 
when  treated  with  bromine :  a  compound  known  as 
diazobenzene  perbromide  is  formed : 

C6H5N2Br3 

1  In  the  absence  of  alkali,  the  reaction  takes  another  course : 

C6H6N2  .  Cl  +  C2H5OH  =  C6H5OC2H5  +  HC1  +  N2 

Phenol  ethers  are  thus  formed. 

2  A  full  account  of  this  process  is  given  in  Meyer-Jacobson,  II, 
155. 


198        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

This,  when  warmed,  breaks  down  into  nitrogen, 
bromine,  and  brombenzene : 

CcHs^Brs  =  C6H5Br  +  N2  +  Br2 

Treated  with  ammonia  it  yields  another  strange  sub- 
stance :  the  three  bromine  atoms  are  replaced  by  one 
atom  of  nitrogen : 


C6H6N2  I  Br3  +  H3  j  N  =  3  HBr  +  C6H6N,  ; 

the  substance  is  known  as  diazobenzene  imide,  and 
forms  a  volatile,  explosive  oil.  Diazobenzene  imide, 
when  reduced  by  zinc  and  sulphuric  acid,  finally 
breaks  down  into  aniline  and  ammonia  : 

C6H5N8  -f  8  H  =  C6H5NH2  +  2  NH3 

We  have  not  yet  reached  the  end  of  Griess's  work 
with  the  diazo  compounds  ;  but  we  must  pause  for  a 
moment  to  consider  the  constitution  of  these  sub- 
stances from  a  contemporary  standpoint.  Griess 
himself  did  not  ponder  much  over  the  problematical 
side  of  the  subject  ;  in  his  first  paper  he  tells  us  all 
he  has  to  say  about  it,  though  he  subsequently 
adhered  to  his  theory  with  stubborn  tenacity.  To 
fully  comprehend  his  point  of  view,  we  must  re- 
member that  in  1860  there  was  no  "benzene  theory" 
upon  which  to  base  other  hypotheses.  Looking, 
then,  at  the  formula  of,  e.g.,  diazobenzene  nitrate, 


Griess  reasoned  as  follows  :  all  ammonia  bases,  such 
as  aniline,  methylamine,  ammonia  itself,  form  salts 
with  acids  by  direct  addition;  the  formula  of 


TEE  DIAZO   COMPOUNDS  199 

diazobenzene   nitrate  therefore   can  be  resolved  as 

follows : 

C6H4N2 .  HN08 

The  complex  C6H4N2  is  the  group  or  radical  which 
corresponds  to  ammonia  or  aniline ;  it  may  be  re- 
garded as  aniline  in  which  three  hydrogen  atoms  are 
replaced  by  one  atom  of  nitrogen,  or  as  benzene  in 
which  two  hydrogen  atoms  are  replaced  by  two 
atoms  of  nitrogen.  The  latter  view  was  the  one 
first  adopted  by  Griess ;  subsequently  he  exchanged 
it  for  the  former.  Both  forms  of  the  theory  involved, 
however,  that  the  group  N2  adhered  to  the  benzene 
ring  in  two  places ;  but  Griess  never  felt  himself  able 
to  specify  the  second  place.  These  views  were 
probably  adopted  without  discussion  until  the  birth 
of  the  benzene  theory  of  Kekule,  when  that  brilliant 
speculator  advanced  a  conception  of  the  diazo  com- 
pounds which  completely  overthrew  Griess's  vague, 
unsatisfactory  assumptions. 

Kekule  based  his  formula1  upon  his  views  of 
valence  and  upon  his  new  benzene  theory.  Nitrogen 
to  him  was  trivalent ;  therefore  two  nitrogen  atoms 
could  not  well  replace  two  atoms  of  hydrogen. 
Moreover,  the  benzene  radical  is  always  C6H5  for 
monosubstituted  derivatives.  Diazobenzene  nitrate 
therefore  must  be  formulated  as  follows  : 

C6H6.N=N.N08 

This  constitution  explains  why  the  decomposition 
reactions  of  diazobenzene  salts  always  yield  mono- 
substitution  products  of  benzene;  if,  according  to 

*  Lehrbuch,  II,  703  (1866). 


200        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Griess,  the  diazo  complex  is  attached  in  two  places, 
substitution  ought  to  occur  twice.  Moreover,  we 
get  a  simple,  comprehensible  formula  for  diazoben- 
zene  perbromide : 

C6H5.N-N-Br 
I      I 
Br  Br 

and  for  diazobenzene  imide : 
C6H5 . 

Ns 

Kekule's  views  are  distinctly  superior  to  Griess's,  and 
were  universally  adopted  —  for  the  time  being,  at 
any  rate  —  except  by  Griess  himself. 

We  can  now  return  to  our  contemplation  of  Griess's 
experimental  investigations.  An  unexpected  turn 
was  given  to  the  chemistry  of  nitrogen  by  the  dis- 
covery that  diazobenzene  has  acid  properties.  Griess 
is  very  much  struck  by  the  fact  that  while  the  intro- 
duction of  a  second  nitrogen  atom  invests  the 
molecule  with  decidedly  greater  basic  properties 
(diazobenzene  is  a  much  stronger  base  than  aniline), 
the  complex  is  also  capable  of  uniting  with  metals 
to  form  substances  resembling  salts.  Thus,  when 
diazobenzene  nitrate  is  treated  with  strong  caustic 
potash,1  the  following  reaction  takes  place  : 

CeHsNaNOs  +  2  KOH  =  CeHsNgOK  +  KN03  +  H2O 

the  products  being  potassium  nitrate  and  diazoben- 
zene potassium.  Solutions  of  this  new  potassium 

lAnn.  Chem.  (Liebig),  137,  53  (1866). 


THE  DIAZO   COMPOUNDS  201 

salt,  treated  with  silver  nitrate,  give  a  precipitate  of 
diazobenzene  silver : 

C6H5N2OK  +  AgN03  =  C6H5N2OAg  +  KNO8 

Griess's  analyses  of  these  compounds  were  branded  as 
questionable  by  Curtius 1  many  years  later.  Curtius 
was  unable  to  prepare  substances  having  the  com- 
position given  by  Griess.  However,  Schraube  and 
Schmidt2  have  recently  shown  that  a  slight  modi- 
fication of  Curtius's  method  will  indeed  yield  pure 
metal  salts  of  diazobenzene ;  and  thus  we  may  feel 
quite  certain  that  Griess  made  sure  of  his  facts 
before  publishing  them.  Diazobenzene  potassium, 
when  treated  with  dilute  acetic  acid,  yields  a  very 
unstable  oil,  which  Griess  looked  upon  as  free  diazo- 
benzene ;  he  formulated  it  thus  : 

C6H4N2 

whereas  Kekule  gave  it  the  following  constitution : 
C6H5N2 .  OH 

As  a  matter  of  fact,  the  oil  was  not  diazobenzene 
at  all,  as  Curtius's3  subsequent  inquiry  proved;  its 
nature  is  still  a  mystery. 

To  sum  up  the  differences  between  Griess's  and 
Kekule's  diazobenzene  formulse  once  more,  the  fol- 
lowing brief  table  will  serve  to  show  the  chief 
distinctions  in  the  two  views : 

1  Ber.  d.  chem.  GeselL  23,  3035  (1890). 

2  I.e.  27,  520  (1894). 


202       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Griess  Kekute 

C6H4N2  C6H5N2  .  OH  Free  diazobenzene 

C6H4N2  .  HC1  C6H5N2  .  Cl  Diazobenzene  chloride 

C6H4N2  .  KOH         C6H6N2  .  OK  Diazobenzene  potassium 

C6H4N2  .  HBr  .  Br2  C6H5NBr  .  NBr  .  Br  Diazobenzene  perbromide1 
C6H4N2  .  NH  C6H5N  -  N  Diazobenzene  iniide 


Griess's  formulae  have  made  no  headway  against 
Kekule's,  and  we  need  not  concern  ourselves  with 
them  further.  The  main  difference  lies  in  Kekule's 
conception  of  diazobenzene  as  a  base  corresponding 
to  ammonium  hydroxide  rather  than  to  ammonia,  as 
the  following  equation  shows  : 

C6H5N2  .  OH  +  HN03  =  C6H6N2  .  N03  +  H20 

But  we  are  not  yet  done  with  our  study  of  Griess's 
discoveries.  Among  the  first  of  his  diazo  compounds 
were  the  diazophenols,  formed  by  diazotizing  amido- 
phenols.  These  diazo  derivatives  are  neutral  sub- 
stances, a  fact  very  well  expressed  by  Kekule's 
formula  of  intramolecular  anhydrides  (analogous  to 
betaine  2)  : 


/ 


O  !  H 


>H1<^ 


H20 


1  Very  recent  investigations  by  Hantzsch  have  shown  that  this 
substance  is  a  genuine  perbromide,  and  that  its  constitution  is 
probably 

C6H5N2Br  .  Br2, 

corresponding  to  caesium  perbromide,  CsBr  .  Br2. 

2  Betaine  is  an  intramolecular  anhydride  of  trimethyl  hydroxy- 
ammoniumacetic  acid  : 


CH2-CO  !  OH 


'N O 

|          I   +H20 
CH2-CO 


THE  DIAZO   COMPOUNDS  203 

Another  class  of  substances  was  brought  to  light 
when  Griess  allowed  two  molecules  of  an  amine  to 
act  upon  one  of  nitrous  acid  : 

2  C6H5NH2  +  HN02  =  (C6H6)2N3H  +  2  H20 

This  substance  was  christened  diazo-amido-benzene ; 
its  investigation  was  a  particularly  brilliant  achieve- 
ment, for  the  regular  methods  of  analysis  were  ren- 
dered impossible  by  the  explosiveness  of  the 
substance.  Griess  found,1  however,  that  when 
treated  with  concentrated  hydrochloric  acid,  diazo- 
amidobenzene  yielded  equal  molecular  quantities  of 
aniline  and  of  chlorbenzene : 

(C6H5)2N8H  +  HC1  =  C6H5C1+N2  +  C6H6NH2 

that  the  amount  of  nitrogen  given  off  on  warming 
with  dilute  acids  corresponds  to  a  molecular  com- 
bination of  diazobenzene  and  aniline ;  and  that 
finally  diazoamidobenzene  is  produced  when  aniline 
and  diazobenzene  salts  are  brought  together.  The 
structure  of  the  substance  is  therefore  expressed  by 
the  following  constitutional  formula  (using  Kekule's 

version) : 

C6H6.N=N-NH.C6H5 

The  decomposition  with  acids  is  shown  thus : 

CljH 

C6H5.N=N-NH.C6H5 


the  molecule  breaking  down  into  aniline  and  diazo- 
benzene, the  latter  then  undergoing  its  own  peculiar 
reactions. 

1  Ann.  Chem.  (Liebig),  181,  257  (1862). 


204        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

It  is  difficult  to  find  a  brighter  bit  of  close  chemical 
reasoning  in  the  whole  field  of  structural  chemistry 
than  this  elucidation  of  the  structure  of  diazoamido- 
benzene  by  Griess  at  a  time  when  the  resources  of 
the  organic  chemist  were  decidedly  limited.  Here 
again  we  find  Griess  carefully  following  up  all  the 
consequences  of  a  given  assumption.  Diazoamido 
compounds  being  formed  by  the  union  of  a  diazo 
compound  with  a  base,  it  should  make  some  dif- 
ference which  base  and  which  diazo  compound  are 
employed  to  synthesize  a  given  diazoamido  deriva- 
tive. Thus,  the  substance  formed  from  aniline  and 
bromdiazobenzene : 


C6H5-NH  [  2  +  Cl !  N=NC6H4Br  =  C6H5-NH-N=N-C6H4Br  +  HC1 

i 1 

ought    to    differ    from    the   diazoamido   compound 
formed  by  union  of  diazobenzene  and  bromaniline  : 


C6H4BrNH  !  2  +  Cl  \  N=NC6H5  =  C6H4Br-NH-N=N-C6H5  +  HC1 

The  difference  in  structure  consists  in  the  different 
location  of  a  hydrogen  atom.  As  a  matter  of  fact, 
Griess1  found  the  two  substances  to  be  identical. 
This  was  one  of  the  first  instances  of  a  phenomenon 
now  quite  familiar  to  us,  viz.  tautomerism.  Laar's 
well-known  hypothesis  (cf.  p.  86)  arose  from  an 
attempt  to  account  for  the  peculiarities  of  diazoamido 
compounds.  It  may  be  said  in  passing  that  the  sub- 
ject of  tautomeric  diazoamido  and  other  closely  allied 
substances  is  engrossing  considerable  attention  at 
present. 

i  Ber.  d.  chem.  Gesell  7,  1618  (1874). 


THE  DIAZO   COMPOUNDS  205 

But  the  end  of  the  diazo  reactions  is  not  yet. 
When  diazobenzene  solutions  are  brought  into  con- 
tact with  phenols  or  tertiary  aromatic  amines,  deriva- 
tives of  azobenzene l  are  formed ;  in  the  one  case 
oxy-azo-compounds : 

C6H6N2C1  +  C6H5OH  =  C6H5-N=N-C6H4OH-f  HC1 
in  the  other  amido-azo-compounds  : 
C6H6N2C1  +  C6HSN(CH3)2  =  C6H5-N=:N-C6H4N(CH3)2  +  HC1 

These  two  derivatives  are  mother-substances  to  an 
enormous  number  of  the  so-called  azo-dyes.  In  this 
connection  we  may  refer  to  a  curious  method  of 
forming  amidoazobenzene  derivatives  from  diazo- 
amido  compounds.  Kekule  2  found  that  diazoamido- 
benzene,  when  warmed  with  a  small  quantity  of  an 
aniline  salt,  is  completely  rearranged  into  amidoazo- 
benzene : 

C6H6-N=N-NH-C6H5    *~    C6H5-N=N-C6H4-NH2 


This  is  a  perfectly  general  reaction  for  all  diazoamido 
compounds.  It  resembles  a  number  of  similar  cases ; 
e.g.  the  formation  of  benzidine  from  hydrazobenzene  : 

CeHs-NH-NH-CeHs  =  H2N-C6H4-C6H4-NH2 

^ *r         <*. 0, 

the  common  feature  of  nearly  all  such  intramolecular 
rearrangements  being  the  formation  of  para-substitu- 

1  The  nomenclature  of  azo  and  diazo  compounds  is  a  trifle  con- 
fusing.    Azo  compounds  contain  the  group  —  N  =  N  — ,  linked  to 
two  carbon  atoms  ;  e.g.  azobenzene  : 

C6H5-N=N-C6H6. 

Diazo  compounds,  on  the  other  hand,  contain  the  group 
C  —  N  =  N  —  X,  where  X  represents  any  element  except  carbon. 

2  Ztschr.  Chem.  1866,  689. 


206       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

tion  products.  No  satisfactory  explanation  of  these 
remarkable  molecular  tornadoes  has  been  advanced. 

We  owe  one  more  curious  class  of  substances  to 
Griess.  When  an  ortho-diamido-benzene  derivative 
is  diazotized,  e.g.  o-phenylene  diamine,1  there  is 
formed  a  sort  of  intramolecular  diazoamido  com- 
pound; one  amido  group  becomes  diazotized,  and 
immediately  hitches  up  with  the  neighboring  amido 

group  : 

,NH2(o)  /NH 

f^     TT    S  \>.  i       TT    r\ 

=     UeM^  \ny-r    +    ±±2^ 

f=N .  OH  Ntf^- 

Griess  assigns  the  following  constitution  to  these 
azimido  compounds : 

-  C«H<I>H 

which  he  defended  against  Zincke's  2  advocacy  of 

'N  % 
NH/ 

For  a  long  time  Griess  seemed  to  have  the  advan- 
tage, but  of  late  it  would  appear  that  Zincke's 
formula  is  a  better  expression  of  the  behavior  of  the 
substituted  azimidobenzenes. 

We  now  pass  to  a  second  stage  in  the  history  of 
diazobenzene.  Heretofore  Kekule's  formulae  have 
reigned  supreme,  Griess  alone  standing  aloof.  But 
a  new  structure  puts  forth  its  claims.  Blomstrand3 
feels  a  discrepancy  between  the  constitutional  for- 

1  Ber.  d.  chem.  Gesell.  5,  200  (1872);  15,  1878  (1882). 

2  Cf.  Ann.  Chem.  (Liebig),  291,  393  (1896). 
8  Cf.  Ber.  d.  chem.  Gesell.  8,  51  (1875). 


THE  DIAZO   COMPOUNDS  207 

mula  of  diazobenzene  arid  those  of  other  nitrogen 
compounds.  Diazobenzene  salts,  he  contends,  are 
true  ammonium  salts.  In  all  ammonium  salts  we 
postulate  the  presence  of  pentavalent  nitrogen; 
witness  ammonium  chloride,  tetra-ethylammonium 
iodide,  etc.: 

H4=N-C1        (C2H5)4=N-I 

No  case  is  known,  says  Blomstrand,  in  which  triva- 
lent  nitrogen  assumes  such  a  role  as  does  the 
nitrogen  of  diazobenzene.  We  may  therefore  regard 
diazobenzene  chloride,  for  example  as  aniline  hydro- 

chlorate  : 

^H8 
C6H5-N^ 

xa 

in  which  the  three  ammonia  hydrogens  have  been 
replaced  by  an  equivalent  nitrogen  atom: 


\C1 

All  diazo  compounds  in  which  the*  characteristic 
basic  reactions  persist  are  formulated  similarly  by 
Blomstrand. 

At  about  the  same  time,  though  without  knowl- 
edge of  Blomstrand's  publication,  Strecker  *  advanced 
the  same  formula,  albeit  for  entirely  different  rea- 
sons. The  atomic  linking  which  Kekule  assumes  in 
diazobenzene  is  also  present  in  the  well-known 
substance  azobenzene  : 


Ber.  d.  chem.  Gesell  4,  780  (1871). 


208       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

It  is  reasonable  to  suppose  that  similarity  of 
structure  implies  similarity  of  chemical  behavior. 
Now,  diazobenzene  and  its  compounds  are  extremely 
unstable,  whereas  azobenzene  and  its  derivatives  are 
quite  stable.  Since  there  can  be  little  doubt  that 
azobenzene  actually  has  the  formula  ascribed  to  it, 
Strecker  advises  the  adoption  of  Blomstrand's  modifi- 
cation as  the  best  expression  of  the  chemical  pecu- 
liarity of  diazobenzene.  A  few  years  later  the  same 
ideas  were  elucidated  by  Erlenmeyer l  in  somewhat 
greater  detail,  without  any  essential  additions  or 
modifications. 

-It  cannot  be  said  that  these  somewhat  radical 
views  made  much  impression  upon  the  chemical 
world.  They  were  barely  discussed;  chemists  be- 
lieved one  way  or  the  other,  much  as  they  felt 
inclined.  The  direct  formation  of  azo  derivatives 
(cf.  p.  205)  from  diazobenzene  salts  did  not  agree 
well  with  the  new  theory,  and  various  assumptions 
as  to  rearrangement  during  this  reaction  became 
necessary.  And  finally,  an  experimental  investiga- 
tion by  Emil  Fischer  seemed  to  triumphantly 
vindicate  the  older  formula. 

Fischer2  found  that  when  diazobenzene  solutions 
act  upon  neutral  potassium  sulphite,  there  is  formed 
a  diazobenzene  sulphonate  : 3 

C6H5N=NC1  +  K2S03  =  C6H5-N=N-S03K  +  KC1 
*If  potassium  acid  sulphite  is  taken,  phenylhydrazine 

1  Ber.  d.  chem.  GeselL  7,  1110  (1874). 

*Ann.  Chem.  (Liebig),  190,  73  (1877). 

8  This  is  distinguished  from  the  following  one  as  Fischer's  salt. 


THE  DIAZO  COMPOUNDS  209 

sulphonic  acid1  is  produced  : 

C6H5N=N-C1  +  2  KHSOg  +  H20  =  C6H6-NH-NH-S03K 

+  KC1  +  H2S04 

These  two  salts  stand  to  each  other  in  the  relation 
expressed  by  the  formulae,  because  the  latter  can  be 
prepared  by  direct  reduction  of  the  former,  the 
former  by  direct  oxidation  of  the  latter.  Fischer's 
salt,  when  hydrolyzed  by  strong  mineral  acids, 
breaks  down  into  a  diazobenzene  salt  and  potassium 
acid  sulphite : 

C6H5N=N  !  S03K  +  HC1  =  C6H6N=NC1  +  KHSOg 

Strecker's  salt,  on  the  other  hand,  yields  potassium 
acid  sulphate  and  phenylhydrazine  : 

C6H5NH-NH-!-S03K  +  H20  =  C6H5NH-NH2  +  K|HS04 

Now,  reasoned  Fischer,  from  the  constitution  of 
phenylhydrazine  we  may  determine  that  of  diazoben- 
zene. According  to  whether  we  start  with  the 
Kekule  or  with  the  Blomstrand  formula,  we  obtain 
the  following  possible  structures  of  phenylhydrazine  : 

Kekule'  Blom  strand 

C6H5N=:N  -  S03K  C6H5N  -  S03K        Diazosulphonate 

III 

N 
C6H5NH-NH-S03K      C6H6NH-S03K     Hydrazine-sulphonate 

II 

NH 
C6H5NH-NH2  C6H5NH2  Phenylhydrazine 

I! 

NH 

The  formula  which  Fischer  deduces  for  phenylhydra- 
zine is  the  one  derived  from  Kekule's  diazobenzene 

1  The  salt  of  this  acid  is  known  as  Strecker's  salt. 


210        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

structure.     The  chief  argument  is  that  the  secondary 
hydrazines,  whose  formula  must  be 


N-NH2 


behave  just  like  phenylhydrazine  itself  toward  most 
reagents  ;  they  must  therefore  have  similar  struc- 
tures. Another  argument  depends  upon  the  prod- 
ucts formed  by  action  of  ethyl  bromide  upon 
phenylhydrazine. 

At  the  time  Fischer's  "hydrazine"  standpoint 
seemed  convincing  and  final.  But  it  is  a  striking 
instance  of  the  change  which  has  come  over  us  to 
realize  that  to-day  we  can  attach  but  little  impor- 
tance to  his  proofs.  Since  we  have  learned  to  esti- 
mate the  nature  and  the  value  of  addition  reactions, 
we  are  much  more  careful  in  forming  conclusions 
about  molecular  structures.  It  would  take  a  bold 
chemist  indeed  to  say  now  just  what  differences  in 
behavior  are  to  be  expected  of  substances  related  as 
are  the  two  phenylhydrazine  formulae  considered 
above.  One  formula  passes  into  the  other  by  the 
simple  shifting  of  a  hydrogen  atom  ;  witness  the 
havoc  wrought  with  structural  conceptions  in  the  case 
of  acetoacetic  ether  (cf.  p.  87).  The  same  plea 
might  now  be  made  for  the  Blomstrand  formula  for 
diazobenzene  ;  once  we  assume  the  intermediate  for- 
mation of  an  addition  product  in  the  formation  of 
azo-dyes,  one  formula  is  as  good  as  the  other. 

And  this  might  have  been  the  final  word  in  the 
diazo  chapter  were  it  not  that  the  last  five  years 
have  brought  us  wealth  of  new  material,  and,  it  must 
be  said,  a  storm  of  error  and  refutation,  of  abuse  and 


THE  DIAZO   COMPOUNDS  211 

counter-abuse.  The  chemical  world  has  seldom  wit- 
nessed a  fiercer  struggle  among  contending  theorists 
than  that  recorded  in  the  pages  of  recent  diazo  his- 
tory. We  cannot  here  concern  ourselves  with  the 
details  of  a  controversy  as  yet  hardly  ended,  nor  with 
the  many  mistakes  and  retractions  made  on  both 
sides.  We  must  be  content  to  hear  each  side  say  its 
say.  and  leave  the  final  decision  to  the  future. 

It  is  said  of  certain  periods  of  scientific  activity 
that  this  or  that  discovery  "was  in  the  air."  This 
theory  of  scientific  contagion  must  certainly  be  appli- 
cable to  the  last  stage  of  diazo  chemistry,  for  on  two 
occasions  important  discoveries  reached  the  light 
simultaneously.  The  first  palpable  intimation  of 
dissatisfaction  with  Kekule's  formula  appeared  from 
von  Pechmann,1  who  assumed  that  diazobenzene 
reacts  as  the  tautomeric  phenylnitrosamine  : 

C6H5-N=N-OH    >-    C6H5-NH-NO 

Diazobenzene  in  alkaline  solution  reacts  with  ke- 
tones ;  e.g.  acetoacetic  ether,  to  form  so-called 
"mixed,"  i.e.  part  fatty,  part  aromatic,  azo  sub- 
stances : 

CH3CO-CH-COOC2H6 
I 
N=N-C6H5 

The  investigation  of  these  mixed  azo  compounds,  in 
which  V.  Meyer,2  von  Pechmann,  and,  above  all, 
Japp  and  Klingemann,3  took  part,  brought  out  the 

i  Ber.  d.  chem.  Gesell  21,  11  (1888). 

2J.c.  25,3190  (1892). 

*Ann.  Chem.  (Liebig),  247,  190  (1888). 


212        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

fact  that  the  name  was  a  misnomer ;  that  in  reality 
these  substances  are  hydrazones, 

CH3CO-C-COOC2H5 
II 
N-NHC6H6 

and  not  azo  bodies.  The  nitrosamine  formula  of 
diazobenzene,  according  to  von  Pechmann,  readily 
explains  this : 

CHsCO  -  C  J  H~2~!  -  COOC2H5 
jO   !N-NHC6H5 

Pursuing  this  idea  experimentally,  von  Pechmann,1 
and,  at  the  same  time,  Wohl,2  found  that  diazoben- 
zene, treated  with  benzoyl  chloride,  yields  nitroso- 
benzanilide ;  a  fact  easily  accounted  for  by  the 
nitrosamine  formula : 

, ,      ,  C6H6N-NO 

C6H6N  i  H  !  -NO  + ;  Cl !  COC6H5  =  |  +  HC1 

COC6H6 

It  is  true,  by  assuming  an  addition  reaction,  it  is 
possible  to  account  for  the  formation  of  nitrosoben- 
zanilide  with  the  regular  diazo  structure,  but  the 
interpretation  seems  a  trifle  forced. 

A  little  later  Bamberger 3  began  the  study  of  the 
oxidation  products  of  diazobenzene.  These  were 
nitrosobenzene,  nitrobenzene,  azobenzene,  diphenyl, 
and  a  substance  called  diazobenzenic  acid.  This 
substance  seems  to  possess  the  structure  of  phenyl- 

nitramine  : 

C6H5NH-N02 

i  Ber.  d.  chem.  Gesell.  25,  3199  (1892). 
2J.c.  3631.  «  i.e.  26,471  (1893). 


rTT 

CALIF 


COMPOUNDS  213 

Its  formation,  however,  can  be  readily  accounted  for 
by  any  diazobenzene  formula,  albeit  easiest  by  that 
of  phenylnitrosamine. 

The  relation  of  diazobenzenic  acid  to  diazobenzene 
assumed  sudden  importance,  and  at  the  same  time 
the  third  era  in  diazo  history  was  begun,  when  three 
different  investigators  simultaneously  discovered 
isomeres  of  the  well-known  diazo  compounds  of 
Griess.  Schraube  and  Schmidt1  found  that  when 
solutions  of  paranitrodiazobenzene  are  treated  with 
an  alkali,  a  salt  is  precipitated  to  which  they  ascribe 

the  formula  : 

/Na 
(p)  (N02)C6H4N< 

\NO 

This  p-nitrophenylnitrosamine  sodium,  when  decom- 
posed by  acetic  acid,  yields  a  substance  isomeric  with 
p-nitrodiazobenzene,  and  which  they  regard  as 
p-nitrophenylnitrosamine  itself  : 

/N02 
C6H4<( 

\NH-NO 

This  substance  is  much  more  stable* than  ordinary 
diazo  compounds  usually  are ;  it  is  difficultly  soluble 
in  water,  and,  above  all,  neither  it  nor  its  sodium 
salt  gives  a  reaction  characteristic  of  all  true  diazo 
compounds,  viz.  to  form  azo-dyes  with  phenols.  If, 
however,  a  mineral  acid  be  added  to  the  solution,  the 
nitrosamine  is  isomerized  to  the  diazo  compound,  and 
this  will  upon  addition  of  alkali  react  normally  to 
form  an  azo-dye.2  This  gives  a  means  for  recogniz- 

1  Ber.  d.  chem.  Gesell  27,  514  (1894). 

2  A  favorite  substance  for  such  tests  is  the  so-called  "K-salt," 
which  is  a  j8-naphtholdisulphonic  acid  (2:3:6). 


214        THE  SPIRIT  OF  OEGANIC  CHEMISTRY 

ing  "  isodiazo  "  compounds  ;  they  will  give  the  usual 
diazo  reaction  only  after  treatment  with  a  mineral 
\acid,  which  isomerizes  them. 

Schraube  and  Schmidt  were  not  able  to  prepare 
the  mother-substance  of  the  isodiazobenzene  series, 
isodiazobenzene  itself  ;  but  they  succeeded  in  convert- 
ing Griess's  diazobenzene  potassium  into  the  isomeric 
isodiazobenzene  potassium  (by  means  of  hot,  concen- 
trated potassium  hydroxide  solutions),  and  found  it 
to  possess  the  characteristic  isodiazo1  reaction. 

The  chief  reasons  for  assigning  the  nitrosamine 
formula  to  the  isodiazo  compounds  are  briefly  thus  : 
In  the  first  place,  p-nitroisodiazobenzene  sodium 
reacts  with  methyl  iodide  to  form  phenylmethyl- 

nitrosainine  : 

/CH8 

< 

\ 


C6H6N 


and  secondly,  the  fact  that  the  nitrosamine  formula 
had  recently  manifested  itself  as  the  "  tautomeric  " 
structure  of  diazobenzene.  However,  von  Pech- 
mann  and  Frobenius,2  who  had  also  discovered  the 
isomerization  of  p-nitrodiazobenzene,  found  that  the 
silver  salt  reacted  differently  with  methyl  iodide, 
producing  not  a  nitrosamine,  but  the  methyl  ester  of 
p-nitrodiazobenzene  : 

C6H5N=N  .  OCH3 

But  this  merely  showed  that  diazo  compounds,  like 
hydrocyanic  acid,  are  true  tautomeric  substances. 

1  Even  carbonic  acid  converts  this  isodiazo    compound   into 
normal  diazobenzene. 

2  Ber.  d.  chem.  Gesell  27,  672  (1894). 


THE  DIAZO   COMPOUNDS  215 

A  third  reason  for  the  nitrosamine  formula  was 
adduced  by  Bamberger,  who  had  also  stumbled 
upon  the  isodiazo  compounds.  Bamberger  found 
that  while  normal  diazo  compounds  are  with  diffi- 
culty oxidized  to  diazobenzenic  acid  (which  he 
regarded  as  phenylnitramine),  the  iso  -derivatives 
are  easily  and  almost  completely  oxidized.  This  is 
very  much  clearer  on  the  basis  of  the  nitrosamine 
formula  for  the  latter,  since  nitroso  compounds  are 
usually  easily  oxidized  to  nitro  bodies  : 

/H  /H 

C6H5N<  -  >•    C6H6N< 

\ 


All  of  a  sudden  a  bombshell  was  dropped  into  the 
diazo  camp.  Hantzsch,1  in  an  elaborate  and  some- 
what pretentious  treatise,  subjected  the  whole  recent 
history  of  the  subject  to  a  critical  review,  and 
arrived  at  the  following  conclusions  :  In  the  first 
place,  there  is  complete  parallelism  in  the  history  of 
the  diazo  compounds  and  the  oximes.  In  the  second 
place,  there  are  no  fully  valid  reasons  i  or  the  nitros- 
amine formula  of  the  isodiazo  compounds  ;  the 
different  behavior  of  the  sodium  and  silver  salts 
when  alkylated  simply  shows  tautomerism  ;  and, 
moreover,  when  the  compounds  of  von  Pechmann 
and  Wohl  (p.  212)  are  saponified,  Bamberger2  ob- 
tained normal  instead  of  isodiazobenzene.  Thirdly, 
normal  and  isodiazo  compounds  have  identical 
structure.  And  fourthly,  since  they  are  structurally 
identical,  the  cause  of  their  isomerism  must  be 
stereochemical.  The  experimental  basis  of  this 

i  Ber.  d.  chem.  Gesell  27,  1702  (1894).  2  j.c.  914. 


216       THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

new  view  was  slight ;  it  consisted  of  nothing  more 
than  the  isolation  of  a  new  diazobenzene  sulphonate 
(of  potassium),  isomeric  with  Fischer's  salt  (p.  208). 
The  new  salt  is  very  unstable,  decomposes  easily, 
and  on  standing  soon  passes  into  the  stable,  older 
isomere.  Hantzsch  took  the  fact  for  granted  that 
these  two  salts  were  structurally  identical,  and 
deduced  for  them  the  following  space  formulae : 

C6H5.N  C6H6.N 

II  II 

S03K  .  N  N .  S03K 

Syn-diazo  compound  Anti-diazo  compound 

The  stereochemistry  of  the  diazo  compounds  is 
then  developed  by  Hantzsch  on  the  basis  of  that  of 
the  oximes  (which  see).  It  will  be  remembered  that 
one  of  the  postulates  of  the  Hantzsch- Werner 
hypothesis  was  that  asymmetry  being  caused  by  a 
nitrogen  double  linking,  it  should  be  expected  among 
such  compounds  as  hydrazones,  azo  compounds,  etc.  : 

C6H5NH .  N=R        C6H5N=rNC6H5 

Owing  to  the  presence  of  two  such  nitrogen  atoms 
in  azo  and  diazo  compounds,  isomerism  of  this  sort 
was  all  the  more  likely.  The  discovery  of  isodiazo 
derivatives  seemed  the  verification  of  the  predictions 
of  1890.  With  reference  to  the  case  in  question,  it 
need  only  be  added  that  Hantzsch  grouped  the 
normal  diazo  compounds,  with  their  tendency  toward 
spontaneous  decomposition,  among  the  syn-deriva- 

tives : 

C6H6N  C6H5N  C6H6N 

II  II                         II 

Cl.N  N08.N  HO.N 


THE  DIAZO  COMPOUNDS  217 

and  the  more  stable  isodiazo  compounds  among  the 
anti-derivatives : 

(N02)C6H4N  C6H4C1N 

II  II 

NOH  NONa 

And  he  added  a  theorem  to  the  effect  that  "  syndiazo 
compounds  couple,1  antidiazo  compounds  do  riot," 
this  being  the  stereochemical  formulation  of  the 
above-described  "  isodiazo  "  reaction. 

It  cannot  be  denied  that  this  publication  produced 
a  deep  impression  upon  the  chemical  public,  an 
impression  which  was  heightened  by  a  further  com- 
munication by  Hantzsch,  in  which  he  described  an 
isomeric  diazoamidobenzene.2  Structurally  speak- 
ing, an  isomeric  diazoamidobenzene  is  impossible, 
and  a  spatial  conception  offered  the  only  explanation. 

The  first  manifestation  of  this  impression  was  a 
vigorous  protest  by  Bamberger.3  The  details  of  this 
careful  arraignment  need  not  be  given  here ;  suffice 
it  to  say  that  Bamberger  showed  conclusively  that 
Hantzsch  had  not  proved  the  assumed  identity  of 
structure  in  his  and  Fischer's  diazosulphonate,  and 
that  the  latter  salt,  which  according  to  Hantzsch 
belongs  to  the  iso  series,  does  not  give  the  isodiazo 
reaction.  Bamberger,  for  his  part,  is  convinced  that 
the  nitrosamine  formula  amply  accounts  for  all 
known  reactions  of  the  isodiazo  compounds.  As  to 
Hantzsch's  isomeric  diazoamidobenzene,  it  was  easy 

1  Coupling  (Kuppeln)  is  the  term  employed  to  designate  reac- 
tions in  which  two  molecules  hitch  together,  as  in  the  formation  of 
azo-dyes. 

2  Ber.  d.  chem.  Gesell.  27,  1857  (1894). 
»  I.e.  2582. 


218        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

to  show  that  it  did  not  exist,1  and  that  the  elaborate 
superstructure  of  conclusions  he  had  based  upon  it 
was  therefore  valueless.  The  isomeric  sulphonates 
are  declared  to  be  isomeric  only  with  reference  to  the 
"  inorganic  "  part  of  the  molecule  : 

X-S03K  X-0-S02K 

The  more  recent  history  of  the  diazo  compounds  is 
too  complicated  for  a  brief  summary  treatment.  In 
large  part  the  details  are  uncertain,  or  even  flatly 
contradict  each  other.  In  this  place  we  can  do  no 
more  than  record  as  much  as  may  be  regarded  as 
positive  facts,  and  let  the  opposing  statements  and 
contentions  get  on  as  best  they  can.  Judgment  has 
not  yet  been  rendered,2  and  until  then  we  must  be 
patient. 

We  must  first  notice  a  view  of  the  isomeric  sul- 
phonates advanced  by  eminent  critical  authorities. 
V.  Meyer  and  P.  Jacobson,  in  their  invaluable 
Lehrbuch,  express  the  conjecture  that  the  differences 
between  Fischer's  and  Hantzsch's  salts  may  be 
explained  by  the  following  formulae  : 


C6H6N=N-  S03K 

\S03K 

the  former  derived  from  Kekule's  diazo  formula,  the 
latter  from  Blomstrand's.     This  view  is  still  shared 

1  Ber.  d.  chem.  Gesell  27,  2596  (1894). 

2  Blomstrand,  J.  prakt.  Chem.  53,  169;  54,  305  (1896);  55,  481 
(1897),  has  given  a  somewhat  partial  though  valuable  objective 
summary  of  the  contending  views  ;  he  declares  in  favor  of  Bam- 
berger's  theory. 


THE  DIAZO   COMPOUNDS  219 

by  many  eminent  thinkers,  although  Hantzsch  has 
rendered  the  actual  structural  identity  of  the  salts  in 
question  extremely  probable  by  a  physico-chemical 
examination  of  their  behavior.1 

A  complication  in  the  situation  next  arose  by  a 
partial  change  of  front  by  Bamberger,2  in  which  he 
became  convinced  that  ordinary  (normal)  diazo  com- 
pounds contain  a  pentavalent  nitrogen  atom ;  and, 
after  advancing  a  view  of  his  own,  which  had  little 
in  its  favor,  gravitated  toward  Blomstrand's  formula 
as  the  best  expression  of  their  properties.  He  calls 

the  radical   C6H5N=N  phenylazonium,   the   radical 

C^{^=^-phenylazo ;  and  modifies  his  views  of 
the  isodiazo  compounds  in  so  far  as  to  drop  the  nitro- 
samine  hypothesis  and  ascribe  to  these  substances 
the  older  Kekule  structure. 

Hantzsch3  meanwhile  endeavored  to  strengthen 
his  position  by  hunting  up  new  cases  of  isomerism : 
he  succeeded  in  finding  isomeric  diazo  cyanides, 
which  are  real  and  not  isocyanides,  and  which  there- 
fore possess  the  same  structure  : 

C1C6H4N2CN 

Hantzsch,  of  course,  regards  these  compounds  as 
stereo-isomeric ;  Bamberger,4  on  the  other  hand,  in- 
terprets them  on  the  Blomstrand-Kekule  basis. 

Hantzsch's  theoretical  views  now  undergo  a  curi- 
ous transformation.  After  declaring  that  the  Blom- 

1  Ber.  d.  chem.  Gesell.  27,  3527  (1894). 

2  I.e.  28,  242,  444  (1895), 
sj.c.  28,666  (1895). 

*  I.e.  28,  826  (1895). 


220       THE  SPIRIT  OF  OEGANIC  CHEMISTRY 

strand  formula  is  absolutely  incompatible 1  with,  the 
behavior  of  diazo  compounds,  and  that  the  sub- 
stances have  different  structures  in  the  solid  state 
and  in  solution,  he  swings  around  completely  and 
admits2  with  Bamberger  that  diazo  salts  with  oxygen 
acids  are  built  on  the  Blomstrand  type  (for  which 
the  name  diazonium  is  proposed  —  this  has  since 
been  universally  adopted).  The  same  is  true  of  the 
other  salts  in  solution:  solutions  of  diazobenzene 
chloride,  for  example,  are  solutions  of  phenyldiazo- 
nium  chloride.  But  solid  diazobenzene  chloride  is 
a  syn-diazo  compound,  and  the  diazo  cyanides  are 
true  stereo-isomeres : 

C6H5N  C6H5N  C6H6N 

II  II  II 

C1N  CN.N  N.CN 

Hantzsch  thus  describes  three  classes  of  diazo  com- 
pounds. 

The  new  turn  affairs  had  taken  was  considerably 
strengthened  by  an  observation  of  Bamberger's. 
When  hydroxylamine  acts  upon  nitrosobenzene : 

C6H5NO  +  H2NOH  =  C6H5N=NOH  +  H20 

the  resulting  compound  is  isodiazobenzene.3  It  may, 
therefore,  be  regarded  as  reasonably  certain  that  this 
substance  has  the  structure  formerly  assigned  by 
Kekule  to  normal  diazobene ;  and  Blomstrand's 
formula  for  the  normal  compound  is  undisputed 
victor  in  the  field. 

With  the  exception  of  a  group  of  substances  to  be 

1  Ber.  d.  chem.  Gesell.  28,  676  (1895). 

2  i.e.  1734.  8  I.e.  1218. 


THE  DIAZO   COMPOUNDS  221 

considered  in  a  moment,  this  is  where  matters  stand 
to-day.  Three  years  have  brought  no  material 
change  in  the  situation.  Bamberger  has  given  no 
sign  that  he  adopts  his  opponent's  theories  ;  Hantzsch 
pursues  his  goal  with  steadfast  persistence.  In  part, 
he  has  shown  that  the  diazo  cyanides  do  exist  in 
three  groups  ;  l  in  addition  to  the  two  supposed 
stereo-isomeres  of  the  phenyl-azo  type,  he  has  ob- 
served signs  of  a  diazonium  cyanide  in  solution.  If 
a  conclusion  may  be  ventured,  the  honors  appear 
to  lie  with  Hantzsch  ;  the  bulk  of  the  evidence  seems 
to  be  in  favor  of  the  stereochemistry  of  diazoben- 
zene,2  and  Bamberger  has  maintained  a  strange 
silence  for  nearly  two  years.  But  as  above  remarked, 
the  final  word  has  not  yet  been  said  on  this  perplex- 
ing subject. 

But  while  the  world  is  now  agreed  upon  Blom- 
strand's  formula  for  normal  diazonium  salts,  no 
agreement  has  been  reached  concerning  the  diazo- 
metallic  salts.  The  experimental  material  upon  this 
phase  of  the  question  is  extremely  complicated,  and 
ill  suited  to  a  brief  statement.  It  must  suffice  to 
give  the  contending  views,  and  leave  the  evidence 
to  further  sifting.  Bamberger  3  looks  upon  the  iso- 
meric  metallic  salts  of  diazobenzene  as  simple  sub- 
stitution products  of  normal  and  isodiazobenzene 
(according  to  his  formulation): 


C6H6N=NONa 


1  Ber.  d.  chem.  Gesell.  30,  2529  (1897). 

2  Cf.  Goldschmidt,  I.e.  28,  2023  (1895). 
8  I.e.  29,  446  (1896). 


222        THE  SPIRIT  OF  ORGANIC  CHEMISTRY 

Hantzsch,1  on  the  other  hand,  sees  in  such  a  com- 
pound as  the  first  a  chemical  impossibility.  To  him, 
a  real  ammonium  hydroxide  simply  cannot  form  such 
salts ;  and  it  must  be  admitted,  the  weight  of  analogy 
is  with  him  in  this  contention.  His  theory  of  these 
compounds  is  that  there  are  no  diazonium  metal 
salts,  and  that  the  isomerism  is  to  be  expressed  only 
by  stereochemical  formulation : 

C6H6N  C6H6N 

II  II 

NaO .  N  N .  ONa 

But  the  world  has  not  yet  passed  the  problem  in 
review ;  and  for  the  present  we  may  believe  as  we 
will,  or  suspend  judgment  in  patient  confidence  that 
ere  long  the  truth  must  prevail. 

i  I.e.  28,  676,  1734  (1895). 


AUTHOR  INDEX 


Anschiitz,  157, 159,  166, 168. 
Armstrong,  52,  58. 
Auwers  and  Dittrich,  180. 

Baeyer,  4,  34,  46,  47,  50,  52,  54,  57, 

75,  84,  93,  96,  109,  113,  115,  152, 

167. 

and  Caro,  85. 

and  Jackson,  16. 

and  Villiger,  48. 

Bamberger,  212,  215,  217,  219,  220, 

221.  • 

Beckmann,  173,  175,  177,  179. 
Behrend,  106, 108. 
Beilstein,  27. 

—  and  Wiegand,  158. 
Bertagnini,  13. 
Bischoff,  167,  185. 
Blomstrand,  207,  218. 
Briihl,  56,  90,  192. 
Butlerow,  22,  115. 

Carlet,  123. 
Caro,  21. 

and  Graebe,  5,  8. 

and  Wanklyn,  4. 

Ceresole,  94. 

Claisen,  72,  76,  81,  83,  85. 

and  Lowman,  74. 

Claus,  49,  53,  185. 
Conrad,  69. 

and  Bischoff,  16. 

Curtius,  201. 

Dafert,  123. 

Dale  and  Schorlemmer,  6. 

Dalton,  190. 

Dewar,  43. 

Drude,  90. 

Dunstan  and  Dymond,  188. 


Elion,  73. 
Erlenmeyer,  157,  208. 

Faraday,  21.      . 

Fischer,  Emil,  98, 100, 104, 109, 110, 

112,  113,  120-144,  147,  149,  153, 

208,  210. 

and  Jennings,  9. 

and  Otto,  6,  7,  9. 

Fittig,  13,  14,  16,  19, 100, 116, 157, 

166. 

and  Jayne,  17,  19. 

and  Ott,  19. 

and  Slocum,  18. 

and  Stuart,  18. 

Franchimont,  151. 
Frankland,  22,  71. 

and  Duppa,  61. 

Freer,  70,  80. 

Gattermann,  196. 

Geuther,  15,  60,  82. 

Goldschmidt,  «.,  72,  85,  173,  181, 

185,  221. 

Gorup-Besanez,  123. 
Graebe,  34. 
Griess,  34,  38,   192,  193,  194,  195, 

198,  200,  202,  204,  206. 
Guthzeit,  88. 

Haller,  71. 

Hantzsch,  57,  186,  202,  215,  217, 

219, 222. 

and  Herrmann,  84. 

and  Werner,  182, 185, 187, 189, 

190. 

Henry,  71. 
Hesse,  71. 

Hofmann,  A.  W.,  2,  4. 
Horbaczewski,  106. 


224 


AUTHOR  INDEX 


Huebner,  15,  31. 

and  Petermaun,  28,  35. 

and  Schneider,  36. 

Jacobson,  P.,  84. 

Japp  and  Klingemann,  211. 

Jungfleisch,  27. 

Kekule',  3,  21,  22,  25,  27,  33,  37,  41, 
58,  199,  205. 

and  Anschiitz,  157, 

Kiliam,  117,  118, 119. 

and  Kleemann,  117. 

Knoeveuagel,  194. 
Knorr,  79,  86,  88. 
Koerner,  34,  38. 
Kolbe,  22,  27, 108,  193. 
Kossel,  112. 
Krusemann,  117. 

Laar,  84,  86,  204. 

Ladenburg,  27,  32,  34,  39,  43,  49. 

and  Engelbrecht,  28. 

Le  Bel,  160. 
Liebig,  154, 157. 

and  Wohler,  109. 

Lippmann,  148. 
Lobry  de  Bruyn,  148. 

and  van  Ekenstein,  148. 

von  Loeben,  105. 
Loew,  124. 
Lessen,  167. 

Maquenne,  151. 

Marburg,  77. 

Marchlewski,  151. 

Markownikoff,  157. 

Medicus,  98. 

Meyer,  V.,  34,  36,  57,  71,  78,  116 

171, 184,  211. 

and  Auwers,  175, 177, 180,  184 

.  and  Demuth,  159. 

and  Jacobson,  218. 

—  and  Schmidt,  116. 

and  Schulze,  117. 

Michael,  72,  75,  77,  84,  150,  165 

168. 

Michaelis,  42. 
von  Miller  and  Plochl,  188. 
Miolati,  10. 
Mitscherlich,  20. 
Muller,  8. 


Nef ,  20,  78,  80,  82,  87. 
Nietzki,  10. 

Pasteur,  127. 

von  Pechmann,  82,  211,  212. 

—  and  Frobenius,  214. 

Perkin,  W.  H.,  Sr.,  1,  12,  14,  16, 

90. 
Piria,  193. 

Raoult,  175. 
von  Richter,  37. 
Rischbieth,  117. 
Rosenstiehl,  4, 10. 

Sachse,  58. 

Salkowsky,  36,  38. 

Sandmeyer,  196. 

Scharvin,  187. 

Schlieper,  93. 

Schmidtmann,  71. 

Schraube  and  Schmidt,  201,  213. 

Skraup,  146,  156,  166, 169. 

Sorokin, 146. 

Stohmann,  56. 

Stone,  144. 

Strecker,  98,  207. 

Tanret,  147. 
Thomson,  56. 
Tollens,  146. 
Traube,  J.,  90. 
Trey,  148. 

van  Been,  123. 
van  t'Hoff,  161, 168. 

and  Le  Bel,  190. 

Vaubel,  58. 

Wedel,  82. 
Weil,  11. 
Wheeler,  85. 

and  Boltwood,  76. 

Williamson,  22. 

Wislicenus,  J.,  60,  62,  65,  69,  160, 

162,  164, 167. 

Wislicenus,  W.,  74,  83,  87. 
Wohl,  117,  144,  212. 
Wohler,  92. 

and  Liebig,  93,  95, 113. 

Wroblewsky,  29,  36. 

Zincke,  36,  206. 


SUBJECT  INDEX 


Acetoacetic  ether : 

condensation    with    isodialuric 
acid,  108. 

condensation    with   diazo  com- 
pounds, 211. 

condensation   with  orthoformic 
ether,  81. 

condensation' with  urea,  106. 

constitution,  63,  81,  83. 

formation,  75. 

hydroxyl  reactions,  82,  83. 

phenylhydrazone,  80. 

sodium  salt,  61,  73,  83. 

syntheses  with,  65-67. 

tautomerism,  86. 
acetone  sodium,  70. 
a-acrite,  125,  127. 
a-acrose,  124,  127. 
addition  theory  (Michael),  76,  78. 
adenin,  112. 
aldo-form,  88. 
aldol  condensation,  75, 125. 
aldose,  122. 
aldoximes,  171, 179. 

determination  of  configuration, 

187. 

allantoin,  99. 
allo-isomerism,  168. 
alloxan,  94,  96. 
alloxantine,  96. 
amidoazobenzene,  205. 
amidoazo  compounds,  205. 
aminocaffeine,  101. 
anisaldoxime,  185. 
apocaffe'ine,  101. 
arabinose,  119. 

configuration,  138. 

formation  from  glucose,  146. 
arabite,  119. 
aromatic  substances,  22. 


aurine,  7,  8. 
azimidobenzene,  206. 
azobenzene,  205,  207. 
azo  compounds,  205. 
"  mixed,"  211. 

Barbituric  acid,  93,  96. 
Beckmann's  rearrangement,   173, 

187. 

benzaldoxime,  174. 
configuration,  186. 
esters,  177. 
reaction  with  phenyl  isocyanate, 

181. 

benzene : 

centric  formula,  52. 
diagonal  formula,  49. 
equivalence  of  hydrogen  atoms, 

32. 

prism  formula,  43. 
stereochemistry,  57. 
symmetry  of  hydrogen  atoms, 

28,  31. 
benzidine,  formation  from  hydra- 

zobenzene,  205. 
benzil  oximes : 
dioximes,  173. 

dioximes,  structure  identity,  175. 
dioximes,  explanation  by  Meyer- 

Auwers,  176. 
dioximes,        explanation        by 

Hantzsch- Werner,  184. 
monoximes,  177. 
benzyl  cyanide,  71. 
beta'ine,  202. 
bromcaffeine,  101. 
bromsuccinic  acids,  158. 


C-derivatives,  72. 
caffeine,  98. 


225 


226 


SUBJECT  INDEX 


caffeine : 

behavior  and  derivatives,  101- 
103. 

formula  (Fischer) ,  101,  111. 

formula  (Medicus),  100,  111. 

synthesis,  112. 
caffoline,  102. 
caff  uric  acid,  101. 
cane  sugar,  149. 
caprolactone,  117. 
carbethoxyacetoacetic  ether,  73. 
chinite,  152. 
chlortheophyllin,  112. 
cinnamic  acid,  14  if. 
compound  sugars,  148. 
condensations  with  sodium  ethyl- 
ate,  74. 

coumarine,  12,  14. 
cyanacetic  ether,  71. 
cyanamide,  95. 

Diacetosuccinic  ether,  66,  78. 
dialuric  acid,  94,  96. 
diazoamido  compounds,  203,  204, 
217. 

conversion  into  amidoazo-,  205. 
diazobenzene : 

imide,  198,  200. 

nitrate,  195,  199. 

perbromide,  197,  200,  202. 

potassium,  200,  214. 

silver,  201. 

sulphonic  acid,  208. 

sulphonic  acid,  isomeric,  216, 218. 
diazobenzenic  acid,  213. 

formation  from  isodiazobenzene, 

215. 
diazo  compounds : 

analysis,  194. 

conversion  into  azo-,  205. 

formation,  193. 

isomerism,  213. 

properties,  194. 

reactions,  196  ff. 

salts,  195. 

salts,  metallic,  200,  202,  221. 

stereoisomeric  cyanides,  219. 

stereoisomerism,  216. 

structure  (Blomstrand),  207,  219, 
220. 


diazo  compounds : 

structure  (Griess),  198,  202. 

structure  (Kekule'),  199,  202. 
diazophenols,  202. 
dibenzoylacetylmethane,  88. 
diethoxybutyric  ether,  81. 
diethoxyhydroxycaffe'ine,  101. 
dilituric  acid,  94,  96. 
dioxy  acetone,  123. 
(p)dioxybenzophenone,  9. 
(p)dioxyhexamethylene,  152. 
dioxyterephthalic  ester,  47. 
dioxyuracil,  108. 
diphenyl,   formation   from   diazo. 

benzene,  197. 

Enol,  88. 
erythrite,  123. 
erythrose,  123. 

Fischer's  salt,  208. 
formaldehyde,  polymerization,  115. 
formose,  124. 
f ormylphenylacetic  ether : 

a-,  87. 

j8-,  88. 

fructose,  119. 
fuchsine,  1. 
f  umaric  acid : 

conversion  into  male'ic  acid,  156. 

molecular  weight,  157. 

properties,  155. 

relation  to  racemic  acid,  157. 

relation  to  succinic  acid,  158. 

stereochemistry,  163  ff. 

Galactose : 

configuration,  140,  143. 

constitution,  118. 
geometric  isomerism,  162  ff. 
glucose : 

configuration,  137-139. 

constitution,  116-118. 

conversion  into  arabinose,  145. 
glucouic  acid,  128. 
glucosides,  149-151. 
glycerinic  aldehyde,  123. 
glycerose,  123. 

polymerization,  125. 


SUBJECT  INDEX 


227 


guanine,  98. 

structure  (Fischer),  111. 

structure  (Medicus) ,  100,  111. 

synthesis,  112. 
gulose,  configuration,  138-139. 

Hantzsch's  salt,  218. 
heptoses,  129. 

hexahydroisophthalic  acid,  48. 
hexahydroterephthalic  acid,  57. 
hexaoxyhexahydrobenzene,  152. 
hydanto'in,  97. 
hydrazobenzene,   conversion   into 

benzidine,  205. 
hydrocaffuric  acid,  102. 
hydrocyanpararosaniline,  8. 
hydroxyeaffeine,  101. 

constitution,  103. 

identity  with,  1,  3,  7 ;  trimethyl- 

uric  acid,  110,  111. 
hydroxylamine,    action    on    alde- 
hydes and  ketones,  171. 
hydurilic  acid,  94,  96. 
hypocaffeme,  102. 
hypoxanthine,  100,  112. 

Idose,  138,  139. 
inosite,  152. 
isatine,  84. 

isobarbituric  acid,  108. 
isobenzaldoxime,  174,  177. 

action  of  phenyl  isocyanate,  181. 

configuration,  186. 

esters,  177. 
isodialuric  acid,  108. 
isodiazo  compounds,  213  ff. 

formation  from  nitrosobenzene, 

220. 

"  isodiazo-reaction,"  213,  214. 
isomaltose,  149. 
isomerism : 

geometric,  162  ff . 

optical,  130  ff. 

problems  of,  154. 
isophenylcrotonic  acid,  16, 17. 

Keto-form,  88. 
ketoses,  122. 
ketoximes,  171, 179. 
configuration,  187. 


Laar's  hypothesis,  86,  89,  204. 
lactames,  lactimes,  84. 
leuco-compounds,  3. 

Male'ic  acid : 

properties,  155. 

anhydride,  155. 

conversion   into   fumaric    acid, 
157. 

relation   to   mesotartaric    acid, 
157. 

relation  to  succinic  acid,  158. 

stereochemistry,  163  ff . 
malonic  ether  synthesis,  69. 
malonitrile,  71. 
maltose,  149. 

manuite,  optical  isomeres,  126. 
mannonic  acid,  125. 

optical  isomeres,  126. 

transformation     into     gluconic 

acid,  128. 
mannose,  125. 

configuration,  138, 139. 
mercaptals  of  the  sugars,  151 . 
mesitylene,  34,  39. 
methylenitane,  115. 
methyluracil,  107. 
milk  sugar,  149. 
monomethyluric  acid,  isomerism, 

105. 

mucic  acid,  140. 
multirotation,  147. 

Naphthalene,  35. 
(m)nitrobenzaldoxime,  185. 
nitrogen,  space  conception,  183. 
(p)nitroisodiazobenzene,  213. 
(p)nitrophenylnitrosamine,  213. 
nitrosobenzanilide  from  diazoben- 

zene,  212. 
nitrosophenol,  85. 
nonose,  129. 

O-derivatives,  72. 
octoses,  129. 
osazones,  121. 

conversion  into  sugars,  122. 
oscillation  hypothesis,  42. 
oxide  formula  of  sugars,  146-147. 


228 


SUBJECT  INDEX 


oximes : 

esters,  172. 

formation,  171. 

isomerism,  173  ff . 

nomenclature,  186. 

reactions,  171. 

stereoisomerism,  182  ff. 

structure-identity,  181. 
oxyazo  compounds,  205. 
oxymethylene  compounds,  77,  83. 
oxyuracil,  107. 

Parabanic  acid,  97. 
pararosaniline,  7. 
pentachlor benzene,  27. 
phenylangelic  acid,  15, 16. 
phenylcrotonic  acid,  15, 17. 
phenylhydrazine,  209,  210. 

action  on  aldehydes  and  ketones, 
120. 

action  on  sugars,  121. 

sulphonic  acid,  209. 
phenylisocyanate  reaction,  181. 
phenylitamalic  acid,  18. 
phenylmethylpyrazoloue,  79. 
phenylnitramine,  212,  215. 
phenylnitrosamine,  211. 
phenyloxypivalinic  acid,  19. 
phenylparaconic  acid,  17. 
phloroglucine,  54,  84. 
phthalic  acid,  35,  48,  54. 
physical  methods  of  determining 

constitution,  56,  90. 
polysaccharides,  148. 
pseudomerism,  89. 
pseudo-uric  acid,  95,  96. 

conversion  into  uric  acid,  109. 
pur  in,  104. 

system  of  nomenclature,  110. 
pyruvic  acid,  non-formation  from 
maleic  acid,  159. 

R-salt,  213. 

riiamnohexonic  acids,  140-142. 
rhamnose,  141. 
rosaniline : 

composition,  2. 

constitution,  8,  10. 

diazo  compound,  4. 


osaniline  : 
salts,  10. 
osolic  acid,  4,  6.^ 

accharic  acid,  136. 

alylic  acid,  27. 

iandmeyer  reaction,  196. 

odium  ethylate  condensation,  74. 

tereochemistry  : 

carbon  tetrahedron,  130. 

general  idea,  161. 

geometrical,  162. 

nitrogen  tetrahedron,  183. 

plane  methods  of  formulation, 
131,  162. 

"preferred"  configuration,  166. 
Strecker's  salt,  209. 
luccinylosuccinic  ester,  47,  82. 
sugars  : 

inversion,  148. 

multirotation,  147. 

nomenclature,  144. 

oxide  formula,  146. 

polysaccharides,  148. 

Talomucic  acid,  141-143. 

talonic  acid,  141-143. 

talose,  141-143. 

tartaric  acid,  configuration,  146. 

tautomerism,  84,  85,  86,  172,  204, 

211,  214. 
theobromine,  98. 

formula  (Fischer),  103,  113. 

formula  (Medicus)  ,  99. 

synthesis,  113. 
theophyllin,  112. 
(m)toluidine,  preparation,  197. 
tolyldiphenylmethane,  6. 
tolylphenylketoxime,  185,  187. 
tribenzoylmethane,  88. 
triketohexamethylene,  54,  84. 
trioxyacrylic  acid,  105. 
triphenylmethane,  6. 

Uracil  derivatives,  107. 
uramidocrotonic  ester,  106. 


uric  acid  : 

formation  from  pseudo-uric  acid, 
109. 


SUBJECT  INDEX 


229 


uric  acid : 

formula  (Baeyer),  96. 
formula    (Fischer),  demonstra- 
tion, 105. 

formula(Fittig),100. 
formula  (Medicus),  99. 
syntheses,  106, 108, 109. 


Violantine,  97. 
violuric  acid,  94,  96. 

Xanthine,  98. 

formula  (Fischer),  103,  111. 

formula  (Medicus),  99,  111. 
xylose,  138. 


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